Fused and Spirocycle Compounds and the Use Thereof

ABSTRACT

The invention relates to fused and spirocycle compounds of Formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R 1 , R 2 , Q 1 -Q 3 , and Z are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat, prevent or ameliorate a disorder responsive to the blockade of calcium channels, and particularly N-type calcium channels. Compounds of the present invention are especially useful for treating pain.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. The inventionrelates to novel fused and spirocycle compounds and the use of thesecompounds as blockers of calcium (Ca²⁺) channels.

2. Background Art

Calcium ions play fundamental roles in the regulation of many cellularprocesses. It is therefore essential that their intracellular levels bemaintained under strict, yet dynamic control (Davila, H. M., Annals ofthe New York Academy of Sciences, pp. 102-117 (1999)). Voltage-gatedcalcium channels (VGCC) serve as one of the important mechanisms forfast calcium influx into the cell. Calcium channels arehetero-oligomeric proteins consisting of a pore-forming subunit (α1),which is able to form functional channels on its own in heterologousexpression systems, and a set of auxiliary or regulatory subunits.Calcium channels have been classified based on their pharmacologicaland/or electrophysiological properties. The classification ofvoltage-gated calcium channels divides them into three groups: (i) highvoltage-activated (HVA) channels, which include L-, N-, P-, and Q-types;(ii) intermediate (IVA) voltage-activated R-type channels; and (iii) lowvoltage-activated (LVA) T-type channels (Davila, supra). Voltage-gatedcalcium channels (VGCC) are also known as voltage-dependent calciumchannels (VDCC) or voltage-sensitive calcium channels (VSCC).

Voltage-sensitive calcium channels (VSCC) regulate intracellular calciumconcentration, which affects various important neuronal functions suchas cellular excitability, neurotransmitter release, hormone secretion,intracellular metabolism, neurosecretory activity and gene expression(Hu et al., Bioorganic & Medicinal Chemistry 8:1203-1212 (2000)). N-typechannels are found mainly in central and peripheral neurons, beingprimarily located on presynaptic nerve terminals. These channelsregulate the calcium flux required for depolarization-evoked release ofa transmitter from synaptic endings. The transmission of pain signalsfrom the periphery to the central nervous system (CNS) is mediated byN-type calcium channels located in the spinal cord (Song et al., J. Med.Chem. 43:3474-3477 (2000)).

The six types of calcium channels (i.e., L, N, P, Q, R, and T) areexpressed throughout the nervous system (Wallace, M. S., The ClinicalJournal of Pain 16:580-585 (2000)). Voltage-sensitive calcium channelsof the N-type exist in the superficial laminae of the dorsal horn andare thought to modulate nociceptive processing by a central mechanism.Blockade of the N-type calcium channel in the superficial dorsal hornmodulates membrane excitability and inhibits neurotransmitter release,resulting in pain relief. Wallace (supra) suggests that based on animalmodels, N-type calcium channel antagonists have a greater analgesicpotency than sodium channel antagonists.

N-type calcium channel blockers have usefulness for neuroprotection andanalgesia. Ziconotide, which is a selective N-type calcium channelblocker, has been found to have analgesic activity in animal models andneuroprotective activity in focal and global ischemia models (Song etal., supra). Examples of known calcium channel blockers includeflunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284,NNC09-0026, and PD 151307 (Hu et al., supra).

Blockade of N-type channels can prevent and/or attenuate subjective painas well as primary and/or secondary hyperalgesia and allodynia in avariety of experimental and clinical conditions (Vanegas, H. et al.,Pain 85:9-18 (2000)). N-type voltage-gated calcium channels (VGCC) playa major role in the release of synaptic mediators such as glutamate,acetylcholine, dopamine, norepinephrine, gamma-aminobutyric acid (GABA)and calcitonin gene-related peptide (CGRP).

Inhibition of voltage-gated L-type calcium channels has been shown to bebeneficial for neuroprotection (Song et al., supra). However, inhibitionof cardiac L-type calcium channels can lead to hypotension. It isbelieved that a rapid and profound lowering of arterial pressure tendsto counteract the neuroprotective effects 30, of L-type calcium channelblockers. A need exists for antagonists that are selective for N-typecalcium channels over L-type calcium channels to avoid potentialhypotensive effects.

U.S. Pat. No. 3,962,259 to Bauer et al. describes1,3-dihydrospiro[isobenzofuran]s that are described to be useful astranquilizers and analgetics.

U.S. Pat. No. 3,686,186 to Houlihan et al. describes substitutedisochroman or phthalan piperidines that are described to be useful ashypotriglyceridemic, anti-hypertensive and antidepressant agents.

U.S. Pat. No. 6,828,440 B2 to Goehring et al. describes spiroindene andspiroindane compounds that are described to exhibit affinity for theORL1 receptor.

U.S. Pat. No. 5,219,860 to Chambers et al. describes spirocycliccompounds that are described to be useful as neuroleptic agents.

U.S. Pat. No. 5,670,509 to Evans et al. describes spiroindane andspiroindene compounds useful as oxytocin receptor antagonists.

U.S. Patent Application Publication No. US 2006/0035884 A1 by Neitzel etal. describes 1′-[(4-chlorophenyl)sulfonyl]spiro[indene-1,4′-piperidine]that is described to be useful for treating cognitive disorders,including Alzheimer's disease.

Published European Patent Application No. 0 444 945 A2 describesspiroindane and spiroindene compounds that are described to be useful inthe treatment and prevention of oxytocin-related disorders.

International Publication No. WO 2006/040329 A1 describes, inter alia,spiroindene and spiroindane compounds that are described to inhibit theactivity of 11βHSD1.

U.S. Pat. No. 3,959,475 to Bauer et al. describes substituted1,3-dihydrospiro(isobenzofuran)s that are described to be useful asantidepressants, tranquilizers and analgetic agents.

U.S. Pat. No. 6,116,209 to Adam et al. describes piperidine derivativesthat are described to be OFQ receptor antagonists.

U.S. Pat. No. 4,233,307 and British Patent Specification No. 1575800both to Ono et al. describe spiro amine derivatives that are describedas having antihypertensive and central nervous system depressantactivity.

BRIEF SUMMARY OF THE INVENTION

The present invention is related to the use of compounds represented byFormula I, below, and the pharmaceutically acceptable salts, prodrugsand solvates thereof, as blockers of calcium (Ca²⁺) channels. Certaincompounds of Formula I show selectivity as N-type calcium channelblockers.

The invention is also related to treating, preventing or ameliorating adisorder responsive to the blockade of calcium channels in a mammalsuffering from excess activity of said channels by administering aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, as described herein.Specifically, the invention is related to treating, preventing orameliorating a disorder responsive to the blockade of N-type calciumchannels in a mammal suffering from excess activity of said channels byadministering an effective amount of a compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof, asdescribed herein.

A number of compounds useful in the present invention have not beenheretofore reported. Thus, one aspect of the present invention isdirected to novel compounds of Formula I, as well as theirpharmaceutically acceptable salts, prodrugs and solvates.

Another aspect of the present invention is directed to the use of thenovel compounds of Formula I, and their pharmaceutically acceptablesalts, prodrugs and solvates, as blockers of N-type calcium channels.

A further aspect of the present invention is to provide a method fortreating, preventing or ameliorating stroke, neuronal damage resultingfrom head trauma, epilepsy, pain (e.g., acute pain, chronic pain, whichincludes, but is not limited to, neuropathic pain and inflammatory pain,or surgical pain), migraine, a mood disorder, schizophrenia, aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), depression, anxiety, apsychosis, hypertension, or cardiac arrhythmia, by administering aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, to a mammal in need of suchtreatment, prevention or amelioration.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating, preventing or ameliorating a disorderresponsive to the blockade of calcium ion channels, especially N-typecalcium ion channels, said pharmaceutical composition containing aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in a mixture with one ormore pharmaceutically acceptable carriers.

Also, an aspect of the present invention is to provide a method ofmodulating calcium channels, especially N-type calcium channels, in amammal, wherein said method comprises administering to the mammal aneffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof.

A further aspect of the present invention is to provide radiolabeledcompounds of Formula I and the use of such compounds, or theirpharmaceutically acceptable salts, prodrugs or solvates, as radioligandsfor their binding site on the calcium channel.

A further aspect of the invention is to provide a method for screening acandidate compound for the ability to bind to a receptor using aradiolabeled compound of Formula I, which includes, but is not limitedto, a ³H, ¹¹C and ¹⁴C radiolabeled compound of Formula I, or apharmaceutically acceptable salt, prodrug or solvate thereof. Thismethod comprises a) introducing a fixed concentration of theradiolabeled compound to the receptor to form a mixture; b) titratingthe mixture with a candidate compound; and c) determining the binding ofthe candidate compound to said receptor.

A further aspect of the invention is to provide the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug or solvatethereof, in the manufacture of a medicament for treating, preventing orameliorating stroke, neuronal damage resulting from head trauma,epilepsy, pain, migraine, a mood disorder, schizophrenia, aneurodegenerative disorder, depression, anxiety, a psychosis,hypertension, or cardiac arrhythmia in a mammal. In a preferredembodiment, the invention provides the use of a compound of Formula I,or a pharmaceutically acceptable salt, prodrug or solvate thereof, inthe manufacture of a medicament for treating, preventing or amelioratingacute pain, chronic pain, or surgical pain.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and will flow from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only and are notrestrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is based on the use of compounds ofFormula I, and the pharmaceutically acceptable salts, prodrugs andsolvates thereof, as blockers of Ca²⁺ channels. In view of thisproperty, compounds of Formula I, and the pharmaceutically acceptablesalts, prodrugs and solvates thereof, are useful for treating disordersresponsive to the blockade of calcium ion channels. In one aspect, ithas been found that certain compounds of Formula I, and thepharmaceutically acceptable salts, prodrugs and solvates thereof,selectively block N-type calcium ion channels and, thus, are useful fortreating disorders responsive to the selective blockade of N-typecalcium ion channels.

The compounds useful in this aspect of the invention are compoundsrepresented by Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R¹ and R² are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, and —C(O)Y, wherein Y is hydroxy,alkoxy, amino, alkylamino, or dialkylamino;

Q¹ is O, —C(O)—, CR²⁰R²⁴, or N—R²⁵;

Q² is —C(O)—, CR²¹R²², or N—R²⁶; and

Q³ is CR² or N; provided that

when Q³ is N, then Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²²;

when Q¹ is O or CR²⁰R²⁴, then Q² is —C(O)— or CR²¹R²², and Q³ is CR²³;

when Q¹ is N—R²⁵, then Q² is —C(O)— and Q³ is CR²³; and

when Q² is N—R²⁶, then Q¹ is —C(O)— and Q³ is CR²³;

R²⁰, R²¹, R²², and R²⁴ are each independently selected from the groupconsisting of hydrogen and alkyl; or

R²⁰ and R²¹ together form a bond and R²² and R²⁴ are independentlyhydrogen or alkyl;

R²³ is hydrogen or alkyl;

R²⁵ and R²⁶ are independently selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl,phenyl, benzyl, and phenethyl, wherein the phenyl ring of any of thephenyl, benzyl and phenethyl groups is optionally substituted with oneor two substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, and haloalkyl;

Z is selected from the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵,wherein:

Z¹ is

Z² is

CR³R⁴—(CH₂)_(n)-D-R⁹;

Z³ is

—SO₂—R¹⁰;

Z⁴ is

and

Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O;

R⁵, R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, anddialkylamino;

R⁹ is selected from the group consisting of

-   -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,        cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or two        substituents in adjacent carbon atoms in the phenyl ring        optionally form a bridge —O—CH₂—O—; and        pyridyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        haloalkyl, halogen, haloalkoxy, and alkoxy; or        -D-R⁹ together forms

R¹⁰ is

-   -   phenyl optionally substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino,        dialkylamino, and alkylcarbonylamino; or    -   1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl        optionally substituted at the nitrogen atom with alkylcarbonyl        or haloalkylcarbonyl;

R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl,mercaptoalkyl, aminoalkyl;

phenyl optionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; and benzyl, wherein the phenyl ring is optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, halogen, and haloalkyl;

R¹³ is hydrogen and R¹⁴ is selected from the group consisting ofhydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, and aminoalkyl;

R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl;

A is —C(O)—, CH₂, or is absent, and B is CH or N; or

A-B is CH═C (where CH is attached to —(CH₂)_(m-));

D is —C(O)— or is absent;

m is 0, 1, 2, 3, 4, or 5;

n is 0, 1, 2, or 3; and

p is 0 or 1.

The groups R¹, R² and R⁵-R⁸, when they are not equal to H, each take theplace of a hydrogen atom that would otherwise be present in any positionon the aryl or heteroaryl ring to which the R group is attached.Similarly, the optional substituents attached to the phenyl and pyridylrings as defined for R⁹, and to the phenyl ring as defined for R¹⁰, R¹¹,R¹², R²⁵ and R²⁶ each take the place of a hydrogen atom that wouldotherwise be present in any position on the phenyl or pyridyl rings.

One group of compounds useful in this aspect of the present inventionare compounds of Formula I as defined above, with the following provisoswhen Q³ is

CR²³:

-   -   1) when Q¹ is O, Q² is —C(O)—, Z is Z¹, and B is CH, then R³ and        R⁴ together form ═O or A is —C(O)—;    -   2) when Q¹ is O, Q² is —C(O)—, Z is Z², and R⁹ is optionally        substituted phenyl, then R³ and R⁴ together form ═O and D is        —C(O)— when n is 1, 2, or 3 or D is absent when n is 0;    -   3) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, or Q¹ is        CR²⁰R²⁴ or —C(O)— and Q² is CR²¹R²², Z is Z¹, A is CH₂ or        absent, and B is CH, then R³ and R⁴ together form ═O;    -   4) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, or Q¹ is        CR²⁰R²⁴ or —C(O)— and Q² is CR²¹R²², Z is Z², n is 0 or 1, and D        is absent, then R⁹ is not an optionally substituted phenyl;    -   5) when Q¹ is CR²⁰R²⁴, Q² is CR²¹R²², and Z is Z³, then R¹⁰ is        not an optionally substituted phenyl;    -   6) when Q¹ is O, Q² is CR²¹R²², Z is Z¹, B is CH, and A is CH₂        or absent, then R³ and R⁴ together form ═O;    -   7) when Q¹ is O, Q² is CR²¹R²², Z is Z¹, B is CH and R³ and R⁴        are both hydrogen, then A is —C(O)—;    -   8) when Q¹ is O, Q² is CR²¹R²², Z is Z², and R⁹ is optionally        substituted phenyl, then R³ and R⁴ together form ═O;    -   9) when Q¹ is O and Q² is CR²¹R²² or —C(O)—, or Q¹ is CR²⁰R²⁴        and Q² is CR²¹R²², where R²⁰ and R²¹ together form a bond, and Z        is Z², then        -D-R⁹ does not together form

or

-   -   10) when Q¹ is —C(O)—, Q² is N—R²⁶, and Z is Z², then R³ and R⁴        together form ═O.

In one embodiment, compounds useful in this aspect of the presentinvention are compounds of Formula I where Q¹-Q³, Z¹-Z⁵, R¹-R¹⁵,R²⁰-R²³, A, B, D, Y, m, n, and p are as described above, with theprovisos that when Q¹ is O, Q² is —C(O)—, and Q³ is CH, and

-   -   1) Z is Z¹ and B is CH, then R³ and R⁴ together form ═O or A is        —C(O)—; or    -   2) Z is Z², then R³ and R⁴ together form ═O and D is —C(O)—, or        R³ and R⁴ together form ═O, D is absent and n is 0;        or a pharmaceutically acceptable salt, prodrug or solvate        thereof.

In one embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is O or CHR²⁰ (i.e., CR²⁰R²⁴, where R²⁴is hydrogen); Q² is —C(O)— or CR²¹R²²; and Q³ is CR²³ or N; providedthat when Q¹ is O, then Q² is —C(O)— and Q³ is CR²³, wherein R²³ ishydrogen or alkyl; and when Q¹ is CHR²⁰, then Q² is CR²¹R²² and Q³ is N,wherein R²⁰ and R²¹ together form a bond, and R²² is hydrogen or alkyl;or a pharmaceutically acceptable salt, prodrug or solvate thereof.

In compounds of Formula I where Z is Z⁴, the carbon to which the—NR¹¹R¹² group is attached can be a chiral center. Accordingly, theconfiguration at that carbon atom can be (R) or (S), with (S) beingpreferred.

In one embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is O, Q^(Z) is —C(O)—, and Q³ is CR²³,i.e, compounds of Formula II:

wherein R¹, R², R²³, and Z are as defined above, and pharmaceuticallyacceptable salts, prodrugs and solvates thereof.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is CR²⁰R²⁴, Q² is CR²¹R²², Q³ is N, andR²⁰ and R²¹ together form a bond, i.e, compounds of Formula III:

wherein R¹, R², R²², R²⁴ and Z are as defined above, andpharmaceutically acceptable salts, prodrugs and solvates thereof.Advantageously, R²² and R²⁴ are both hydrogen. Useful compounds ofFormula III include those where R²² and R²⁴ are independently hydrogenor C₁₋₄ alkyl, preferably hydrogen, methyl or ethyl. Preferably, eitherR²² or R²⁴ is hydrogen and the other one is hydrogen or methyl, and morepreferably R²² and R²⁴ are both hydrogen.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is CR²⁰R²⁴, Q² is CR²¹R²², Q³ is N, andR²⁰, R²¹, R²², and R²⁴ are each independently hydrogen or alkyl, i.e,compounds of Formula IV:

wherein R¹, R², and Z are as defined above, and pharmaceuticallyacceptable salts, prodrugs and solvates thereof. Useful compounds ofFormula IV include those where R²⁰, R²¹, R²², and R²⁴ are eachindependently hydrogen or C₁₋₄ alkyl, preferably hydrogen, methyl orethyl. Preferably, R²⁰ and R²¹ are both hydrogen and R²² and R²⁴ areindependently hydrogen, methyl or ethyl, more preferably hydrogen ormethyl. More preferably R²⁰, R²¹, R²², and R²⁴ are each hydrogen.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is CR²⁰R²⁴, Q² is CR²¹R²², Q³ is CR²³,and R²⁰, R²¹, R²², R²³ and R²⁴ are each independently hydrogen or alkyl,i.e, compounds of Formula V:

wherein R¹, R², R²³, and Z are as defined above, and pharmaceuticallyacceptable salts, prodrugs and solvates thereof. Useful compounds ofFormula V include those where R²⁰, R²¹, R²², and R²⁴ are eachindependently hydrogen or C₁₋₄ alkyl, preferably hydrogen, methyl orethyl. Preferably, R²⁰ and R²¹ are both hydrogen and R²² and R²⁴ areindependently hydrogen, methyl or ethyl, more preferably hydrogen ormethyl. More preferably R²⁰, R²¹, R²², and R²⁴ are each hydrogen.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is CR²⁰R²⁴, Q² is CR²¹R²², Q³ is CR²³,R²⁰ and R²¹ together form a bond, i.e, compounds of Formula VI:

wherein R¹, R², R²², R²³, R²⁴, and Z are as defined above, andpharmaceutically acceptable salts, prodrugs and solvates thereof. Usefulcompounds of Formula VI include those where R²² and R²⁴ areindependently hydrogen or C₁₋₄ alkyl, preferably hydrogen, methyl orethyl. Preferably, either R²² or R²⁴ is hydrogen and the other one ishydrogen or methyl, and more preferably R²² and R²⁴ are both hydrogen.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is O, Q² is CR²¹R²², and Q³ is CR²³,i.e, compounds of Formula VII:

wherein R¹, R², R²², R²¹, and Z are as defined above, andpharmaceutically acceptable salts, prodrugs and solvates thereof. Usefulcompounds of Formula VII include those where R²¹ and R²² areindependently hydrogen or C₁₋₄ alkyl, preferably hydrogen, methyl orethyl. Preferably, R²¹ is hydrogen and R²² is hydrogen or methyl, andmore preferably R²¹ and R²² are both hydrogen.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is N—R²⁵, Q² is —C(O)—, and Q³ is CR²³,i.e, compounds of Formula VIII:

wherein R¹, R², R²³, R²⁵, and Z are as defined above, andpharmaceutically acceptable salts, prodrugs and solvates thereof.

In a further embodiment, compounds useful in the present invention arecompounds of Formula I where Q¹ is —C(O)—, Q² is N—R²⁶, and Q³ is CR²³,i.e, compounds of Formula IX:

wherein R¹, R², R²³, R, and Z are as defined above, and pharmaceuticallyacceptable salts, prodrugs and solvates thereof.

Useful compounds of any of Formulae I-IX, as described above, includethose where R¹ and R² are each independently hydrogen or C₁₋₄ alkyl.Preferably, R¹ and R² are both hydrogen.

In compounds of Formula I where Q³ is CR²³, R²³ is preferably hydrogenor C₁₋₄ alkyl, more preferably hydrogen.

Useful compounds of any of Formulae I, VIII, and IX, include those whereR²⁵ and R²⁶ are each independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl,halo(C₁₋₆)alkyl, C₃₋₆ cycloalkyl, phenyl, benzyl, and phenethyl, whereinthe phenyl ring of any of the phenyl, benzyl and phenethyl groups isoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,and halo(C₁₋₄)alkyl; preferably each independently selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkyl, halo(C₁₋₄)alkyl, C₃₋₅ cycloalkyl, phenyl, benzyl, andphenethyl, wherein the phenyl ring of any of the phenyl, benzyl andphenethyl groups is optionally substituted with one or two substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, halogen, and halo(C₁₋₄)alkyl. More preferably R²⁵ and R²⁶ areindependently selected from the group consisting of hydrogen; methyl;ethyl; propyl; isopropyl; butyl; tert-butyl; hydroxymethyl;hydroxyethyl; methoxymethyl; methoxyethyl; ethoxymethyl; fluoromethyl;difluoromethyl; trifluoromethyl; chloromethyl; chloroethyl; cyclopropyl;unsubstituted phenyl; unsubstituted benzyl; unsubstituted phenethyl;phenyl substituted with one or two substituents independently selectedfrom the group consisting of methyl, ethyl, isopropyl, methoxy, ethoxy,halogen, fluoromethyl, difluoromethyl, and trifluoromethyl; benzylsubstituted at the phenyl ring with one or two substituentsindependently selected from the group consisting of methyl, ethyl,isopropyl, methoxy, ethoxy, halogen, fluoromethyl, difluoromethyl, andtrifluoromethyl; and phenethyl substituted at the phenyl ring with oneor two substituents independently selected from the group consisting ofmethyl, ethyl, isopropyl, methoxy, ethoxy, halogen, fluoromethyl,difluoromethyl, and trifluoromethyl. Useful compounds of the inventioninclude those where R²⁵ and R²⁶ are each independently hydrogen,unsubstituted benzyl, or benzyl substituted at the phenyl ring with oneor two substituents independently selected from the group consisting ofmethyl, ethyl, isopropyl, methoxy, ethoxy, halogen, fluoromethyl,difluoromethyl, and trifluoromethyl. Advantageously, R²⁵ and R²⁶ areindependently hydrogen or unsubstituted benzyl.

Useful compounds of Formula I that may be employed in the method of thepresent invention include those, as described above, where R³ and R⁴ areboth hydrogen when Z is Z¹, A is CH₂ or absent and B is CH.

Further useful compounds include those where Q¹ is O, Q² is —C(O)—, Q³is CR²³ and R³ and R⁴ are both hydrogen when Z is Z¹, A is —C(O)—, CH₂,or absent and B is N.

Useful compounds where R³ and R⁴ are both hydrogen include those where Zis Z² and n is 0.

Further useful compounds include those where Z is Z² and

-D-R⁹ together forms

Preferably, in these compounds both R³ and R⁴ are hydrogen. Preferably,in these compounds Q¹ is CR²⁰R²⁴, where R²⁴ is hydrogen, Q² is CR²¹R²²,and Q³ is N.

-   -   Useful compounds include those where R³ and R⁴ together form ═O        and Z is Z¹.

In one embodiment, compounds useful in the present invention arecompounds of any one of Formulae I-IX where Z is Z¹. Preferably, R⁵, R⁶,R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, cyano, amino,alkylamino, and dialkylamino. More preferably, R⁵, R⁶, R⁷ and Rare eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₆)alkyl, hydroxy, cyano, amino, anddi(C₁₋₆) alkylamino; and more preferably independently selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen,halo(C₁₋₃)alkyl, hydroxy, cyano, amino, and di(C₁₋₃)alkylamino.Advantageously, R⁵, R⁶, R⁷ and R⁸ are each independently selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, halogen, especially fluorine, trifluoromethyl, hydroxy,cyano, and amino.

Useful compounds include those where R⁵ and R⁷ are both hydrogen and R⁶and R⁸ are as defined above. Further useful compounds include thosewhere R⁵ and R⁷ are both hydrogen and R⁶ and R⁸ are independentlyselected from the group consisting of hydrogen, methyl, ethyl, propyl,isopropyl, halogen, methoxy, ethoxy, trifluoromethyl, cyano, amino, anddimethylamino. Advantageously, R⁵ and R⁷ are both hydrogen and R⁶ and R⁸are both fluorine. Preferably, either or both R⁶ and R⁸ are at thepara-position of the respective phenyl rings.

In one embodiment, compounds useful in the present invention arecompounds of any one of Formulae I-IX where Z is Z². Useful compoundsinclude those where R⁹ is phenyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano,amino, aminoalkyl, alkylamino, and dialkylamino; preferablyindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino; andmore preferably independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₃)alkyl, halo(C₁₋₃)alkyloxy, amino,C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino. Advantageously, R⁹ is phenyloptionally substituted with one or two substituents independentlyselected from the group consisting of methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, halogen, especially fluorine, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy, and dimethylamino. Usefulcompounds include those where R⁹ is phenyl substituted with one or twosubstituents as defined above.

Useful compounds include those where R⁹ is pyridyl, especially 2- or3-pyridyl, optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, haloalkyl,halogen, haloalkoxy, and alkoxy; preferably independently selected fromthe group consisting of alkyl, alkoxy; and haloalkoxy; and morepreferably selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkoxy, and halo(C₁₋₃)alkyloxy. Advantageously, R⁹ is pyridyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,trifluoromethoxy, and 2,2,2-trifluoroethoxy. Useful compounds includethose where R⁹ is pyridyl substituted with one or two substituents asdefined above.

In one embodiment, compounds useful in the present invention arecompounds of any one of Formulae I-IX where Z is Z³. Useful compoundsinclude those where R¹⁰ is phenyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,and alkylcarbonylamino; preferably independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, halo(C₁₋₃)alkyl,halo(C₁₋₃)alkyloxy, amino, C₁₋₃ alkylamino, di(C₁₋₃)alkylamino, and C₁₋₃alkylcarbonylamino; and more preferably independently selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,trifluoromethoxy, and 2,2,2-trifluoroethoxy.

Useful compounds include those where R¹⁰ is 1,2,3,4-tetrahydroquinolinylor 1,2,3,4-tetrahydroisoquinolinyl optionally substituted at thenitrogen atom with alkylcarbonyl or haloalkylcarbonyl; preferablyoptionally substituted with C₁₋₃ alkylcarbonyl orhalo(C₁₋₃)alkylcarbonyl. Advantageously, R¹⁰ is1,2,3,4-tetrahydroisoquinolinyl, preferably1,2,3,4-tetrahydroisoquinolin-6-yl, optionally substituted at thenitrogen atom with halo(C₁₋₃)alkylcarbonyl, preferablytrifluoromethylcarbonyl or 2,2,2-trifluoroethylcarbonyl.

In one embodiment, compounds useful in the present invention arecompounds of any one of Formulae I-IX where Z is Z⁴. Preferably, R¹¹ andR¹² are each independently selected from the group consisting ofhydrogen; alkyl; alkoxycarbonyl; phenyl optionally substituted with oneor two substituents independently selected from the group consisting ofalkyl, alkoxy, halogen and haloalkyl; and benzyl optionally substitutedat the phenyl ring with one or two substituents independently selectedfrom the group consisting of alkyl, alkoxy, halogen and haloalkyl. Morepreferably, R¹¹ and R¹² are each independently selected from the groupconsisting of C₁₋₆ alkyl; C₁₋₆ alkoxycarbonyl; phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, andhalo(C₁₋₃)alkyl; and benzyl optionally substituted at the phenyl ringwith one or two substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, and halo(C₁₋₃)alkyl.Advantageously, R¹¹ and R¹² are independently selected from the groupconsisting of methyl; ethyl; propyl; iso-propyl; butyl; tert-butyl;methoxycarbonyl; ethoxycarbonyl; propoxycarbonyl; iso-propoxycarbonyl;tert-butoxycarbonyl; phenyl optionally substituted with methyl, ethyl,iso-propyl, methoxy, ethoxy, halogen, fluoromethyl, difluoromethyl, ortrifluoromethyl; and benzyl optionally substituted at the phenyl ringwith methyl, ethyl, iso-propyl, methoxy, ethoxy, halogen, fluoromethyl,difluoromethyl, or trifluoromethyl.

R¹⁴ is preferably selected from the group consisting of alkyl,hydroxyalkyl, alkoxyalkyl, haloalkyl, and aminoalkyl. More preferably,R¹⁴ is selected from the group consisting of straight chain C₁₋₆ alkyl,branched chain C₃₋₆ alkyl, and hydroxy(C₁₋₆)alkyl. Useful compoundsinclude those where R¹⁴ is methyl, ethyl, propyl, iso-propyl, butyl,tert-butyl, sec-butyl, or iso-butyl.

In one embodiment, compounds useful in the present invention arecompounds of any one of Formulae I-IX where Z is Z⁵, Preferably, R¹⁵ isselected from the group consisting of 2-benzo[b]thienyl,3-benzo[b]thienyl, 1-benzo[c]thienyl, 3-benzo[c]thienyl, 2-benzofuryl,3-benzofuryl, 1-isobenzofuryl, and 3-isobenzofuryl; more preferablyselected from the group consisting of 2-benzo[b]thienyl,3-benzo[b]thienyl, 1-benzo[c]thienyl, and 3-benzo[c]thienyl.

Useful compounds of any of Formulae I-IX include those where m is 0, 1or 2. In one aspect, useful compounds of the present invention includethose where m is 0, 1, or 2 and A is CH₂ or —C(O)—.

Useful compounds of any of Formulae I-IX include those where n is 0, 1,or 2.

Preferably, p is 0.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula II include those represented by Formula X:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², and Z are as defined above. Advantageously, R¹ and R²are both hydrogen.

In one aspect, preferred compounds falling within the scope of Formula Xare compounds represented by Formula XI:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R³-R⁸, A, and m are as defined above. Preferred values forR³-R⁸, A, and m are those described above for Formula I. Especiallyuseful compounds of Formula XI include those where R³ and R⁴ are bothhydrogen. Advantageously, A is CH₂ or absent.

In one aspect of the present invention, preferred compounds fallingwithin the scope of Formula X useful in the present invention arecompounds represented by Formula XII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R³-R⁸, A, and m are as defined above. Another group of compoundsuseful in this aspect are compounds of Formula XII where either R³ andR⁴ together form ═O or A is —C(O)—. Preferred values for R³-R⁸, A, and mare those described above for Formula I.

Useful compounds of Formula XII include those where R³ and R⁴ togetherform ═O and A is CH₂ or absent.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula III include those represented by FormulaXIII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², and Z are as defined above. Advantageously, R¹ and R²are both hydrogen.

The invention also relates to fused and spirocycle compounds fallingwithin the scope of Formula XIII represented by Formula XIV:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Preferred values forR³-R⁸, A, B, and m are those described above for Formula I.

Useful compounds of Formula XIV include those where R³ and R⁴ are bothhydrogen. In these compounds, B is preferably CH. Advantageously, R³ andR⁴ are both hydrogen, B is CH, and A is CH₂ or absent in compounds ofFormula XIV.

Further useful compounds of Formula XIV include those where R³ and R⁴together form ═O. In these compounds, B is preferably CH or A-B is CH═C.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula IV include those represented by Formula XV:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², and Z are as defined above. Advantageously, R¹ and R²are both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XV represented by FormulaXVI:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Preferred values forR³-R⁸, A, B, and m are those described above for Formula I.

Useful compounds of Formula XVI include those where R³ and R⁴ are bothhydrogen. In these compounds, B is preferably CH. Advantageously, R³ andR⁴ are both hydrogen, B is CH, and A is CH₂ or absent in compounds ofFormula XVI.

Further useful compounds of Formula XVI include those where R³ and R⁴together form ═O. In the compounds, B is preferably CH and A is CH₂ orabsent.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula V include those represented by Formula XVII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², and Z are as defined above. Advantageously, R¹ and R²are both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XVII represented byFormula XVIII:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Another group ofcompounds useful in this aspect are compounds of Formula XVIII where Ais CH₂ or absent, B is CH; and R³ and R⁴ together form ═O. Preferredvalues for R³-R⁸, A, B, and m are those described above for Formula I.

Useful compounds of Formula XVIII include those where A-B is CH═C.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula VI include those represented by Formula XIX:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², and Z are as defined above. Advantageously, R¹ and R²are both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XIX represented by FormulaXX:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Another group ofcompounds useful in this aspect are compounds of Formula XX where A isCH₂ or absent, B is CH, and R³ and R⁴ together form ═O. Preferred valuesfor R³-R⁸, A, B, and m are those described above for Formula I.

Useful compounds of Formula XX include those where A-B is CH═C.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula VII include those represented by FormulaXXI:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R, R² and Z are as defined above. Advantageously, R¹ and R² areboth hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XXI represented by FormulaXXII:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Another group ofcompounds useful in this aspect are compounds of Formula XXII where B isCH, A is CH₂ or absent, and R³ and R⁴ together form ═O. A further groupof useful compounds include compounds of Formula XXII where B is CH, R³and R⁴ are both hydrogen, and A is —C(O)—. Preferred values for R³-R⁸,A, B, and m are those described above for Formula I.

Useful compounds of Formula XXII include those where R³ and R⁴ togetherform ═O and A is CH₂ or absent.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula VIII include those represented by FormulaXXIII:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², R²⁵ and Z are as defined above. Advantageously, R¹ andR² are both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XXIII represented byFormula XXIV:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Preferred values forR³-R⁸, R²⁵, A, B, and m are those described above for Formula I.

Useful compounds of Formula XXIV include those where R²⁵ is hydrogen orbenzyl. In these compounds, B is preferably CH. Advantageously, R³ andR⁴ are both hydrogen, B is CH, and A is CH₂ or absent in compounds ofFormula XXIV.

In one embodiment, useful compounds of the present invention fallingwithin the scope of Formula IX include those represented by Formula XXV:

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², R²⁶ and Z are as defined above. Advantageously, R¹ andR² are both hydrogen.

In one embodiment, compounds useful in the present invention arecompounds falling within the scope of Formula XXV represented by FormulaXXVI:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined above. Preferred values forR³-R⁸, R²⁶, A, B, and m are those described above for Formula I.

Useful compounds of Formula XXVI include those where R²⁶ is hydrogen orbenzyl. In these compounds, B is preferably CH. Advantageously, R³ andR⁴ are both hydrogen, B is CH, and A is CH₂ or absent in compounds ofFormula XXVI.

Exemplary compounds that may be employed in the methods of the presentinvention include:

-   1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-(3,3-diphenylpropanoyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-{2-[N,N-bis(4-fluorophenyl)aminocarbonyl]ethyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-{2-[N,N-bis(4-fluorophenyl)aminocarbonyl]ethan-1-oyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-[N,N-bis(4-fluorophenyl)aminocarbonylmethyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-{3-[N,N-bis(4-fluorophenyl)amino]propyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-[4-(4-fluorophenyl)-4-oxobutanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-(4-trifluoromethylphenylsulfonyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-(4-methoxy-3-trifluoromethylbenzoyl)-spiro-[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl    carbonyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-(6-methoxypyridin-3-ylcarbonyl)-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-[4-methyl-2-(N-methyl-N-tert-butoxycarbonylamino)-pentanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one;-   1,3-dihydro-1′-{4-methyl-2-[N-methyl-N-(4-methoxybenzyl)amino]-pentanoyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one;    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Other exemplary compounds useful in the methods of the present inventioninclude:

-   1-(4,4-bis(4-fluorophenyl)butyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(3,3-diphenylpropanoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4,4-bis(4-fluorophenyl)-but-3-enoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4,4-bis(4-fluorophenyl)butanoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-dimethylaminobenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-isopropylbenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-methoxy-3-trifluoromethylbenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-isopropylbenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-methoxybenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylmethenyl)ethyl]-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(benzo[b]thiophen-2-ylcarbonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(N-trifluoromethylcarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl-sulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyidine];-   1-(4-trifluoromethylphenylsulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Further exemplary compounds useful in the methods of the presentinvention include:

-   1-[4,4-bis(4-fluorophenyl)butyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-[4,4-bis(4-fluorophenyl)butanoyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(4-iso-propylbenzyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];-   1-(3-tri    fluoromethyl-4-methoxyphenyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Further exemplary compounds useful in the methods of the presentinvention include:

-   1-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene];-   1-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indene];-   1-(methoxybenzyl)-spiro[piperidine-4,1′-indene];-   1-(3-tri    fluoromethyl-4-methoxybenzoyl)-spiro[piperidine-4,1′-indene];-   1-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indane];-   1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isobenzofuran-1,4′-piperidine];    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Further exemplary compounds useful in the methods of the presentinvention include:

-   2-benzyl-2,3-dihydro-1′-[4,4-bis(fluorophenyl)butyl]-spiro[isoindole-1,4′-piperidine]-3-one;-   2,3-dihydro-1′-[4,4-bis(fluorophenyl)butyl]-spiro[isoindole-1,4′-piperidine]-3-one;-   2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine];-   1-benzyl-2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine];    and the pharmaceutically acceptable salts, prodrugs and solvates    thereof.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful cycloalkyl groups are selected from C₃₋₁₂ cycloalkyl; preferablyC₃₋₆ cycloalkyl. Typical cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, 3-pentyl, hexyl and octyl groups.

Useful alkenyl groups are C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl.Typical C₂₋₄ alkenyl groups include ethenyl, propenyl, isopropenyl,butenyl, and sec-butenyl.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms (e.g., fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl andtrichloromethyl groups).

Useful hydroxyalkyl groups include C₁₋₁₀ alkyl groups substituted byhydroxy (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups).

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkoxycarbonyl groups include carbonyl groups, —C(O)—,substituted by any of the above mentioned alkoxy groups (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl,and tert-butoxycarbonyl).

Useful haloalkoxy groups include oxygen substituted by one of the C₁₋₁₀haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy,and trifluoromethoxy).

Useful alkylamino and dialkylamino groups are —NHR²⁷ and —NR²⁷R²⁸,wherein R²⁷ and R²⁸ are each independently selected from a C₁₋₁₀ alkylgroup.

Useful alkylcarbonyl groups include carbonyl groups, —C(O)—, substitutedby any of the above mentioned alkyl groups (e.g., methylcarbonyl, i.e.,methanoyl, ethylcarbonyl, propoxycarbonyl, iso-propoxycarbonyl, andtert-butoxycarbonyl).

Useful alkylcarbonylamino groups include carbonylamino groups, —C(O)NH—,substituted with any of the above mentioned alkyl groups (e.g.,methylcarbonylamino and ethylcarbonylamino).

Useful haloalkylcarbonyl groups include carbonyl groups substituted withany of the above mentioned haloalkyl groups (e.g.,trifluoromethylcarbonyl).

Useful mercaptoalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —SH group.

Useful alkylthioalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by a —S(C₁₋₁₀)alkyl group, and preferablysubstituted by a —S(C₁₋₄)alkyl group.

As used herein, the term “amino” or “amino group” refers to —NH₂.

As used herein, the term “optionally substituted” refers to a group thatmay be unsubstituted or substituted.

The invention disclosed herein is also meant to encompass prodrugs ofany of the disclosed compounds. As used herein, prodrugs are consideredto be any covalently bonded carriers that release the active parent drugin vivo. Non-limiting examples of prodrugs include esters or amides ofcompounds of Formula I-XXVI having hydroxyalkyl or aminoalkyl as asubstituent, and these may be prepared by reacting such parent compoundswith anhydrides such as succinic anhydride.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may result,for example, from the oxidation, reduction, hydrolysis, amidation,esterification and the like, of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also intended to encompass thedisclosed compounds being isotopically-labelled (i.e., radiolabeled) byhaving one or more atoms replaced by an atom having a different atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, andpreferably ³H, ¹¹C, and ¹⁴C. Isotopically-labeled compounds of thepresent invention can be prepared by methods known in the art.

The present invention is also directed specifically to ³H, ¹¹C, or ¹⁴Cradiolabeled compounds of any of Formulae I-XXVI, as well as theirpharmaceutically acceptable salts, prodrugs and solvates, and the use ofany such compounds as radioligands for their binding site on the calciumchannel. For example, one use of the labeled compounds of the inventionis the characterization of specific receptor binding. Another use of alabeled compound of the present invention is an alternative to animaltesting for the evaluation of structure-activity relationships. Forexample, the receptor assay may be performed at a fixed concentration ofa labeled compound of the invention and at increasing concentrations ofa test compound in a competition assay. For example, a tritiatedcompound of any of Formulae I-XXVI can be prepared by introducingtritium into the particular compound, for example, by catalyticdehalogenation with tritium. This method may include reacting a suitablyhalogen-substituted precursor of the compound with tritium gas in thepresence of a suitable catalyst, for example, Pd/C, in the presence orabsence of a base. Other suitable methods for preparing tritiatedcompounds can be found in Filer, Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is meant toencompass the uses of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers maybe separated according to methods known to those of ordinary skill inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are intended to beencompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The invention disclosed herein also encompasses the use of salts of thedisclosed compounds, including all non-toxic pharmaceutically acceptablesalts thereof of the disclosed compounds. Examples of pharmaceuticallyacceptable addition salts include inorganic and organic acid additionsalts and basic salts. The pharmaceutically acceptable salts include,but are not limited to, metal salts such as sodium salt, potassium salt,cesium salt and the like; alkaline earth metals such as calcium salt,magnesium salt and the like; organic amine salts such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and thelike; inorganic acid salts such as hydrochloride, hydrobromide,phosphate, sulphate and the like; organic acid salts such as citrate,lactate, tartrate, maleate, fumarate, mandelate, acetate,dichloroacetate, trifluoroacetate, oxalate, formate and the like;sulfonates such as methanesulfonate, benzenesulfonate,p-toluenesulfonate and the like; and amino acid salts such as arginate,asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularcompound of the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, andthe like. Basic salts can be formed by mixing a solution of the compoundof the present invention with a solution of a pharmaceuticallyacceptable non-toxic base such as sodium hydroxide, potassium hydroxide,choline hydroxide, sodium carbonate and the like.

The invention disclosed herein is also meant to encompass solvates ofany of the disclosed compounds. One type of solvate is a hydrate.Solvates do not significantly alter the physiological activity ortoxicity of the compounds, and as such may function as pharmacologicalequivalents.

Since compounds of Formulae I-XXVI are blockers of calcium (Ca²⁺)channels, a number of diseases and conditions mediated by calcium ioninflux can be treated by employing these compounds. The presentinvention is thus directed generally to a method for treating,preventing or ameliorating a disorder responsive to the blockade ofcalcium channels, and particularly the selective blockade of N-typecalcium channels, in an animal suffering from, or at risk of sufferingfrom, said disorder, said method comprising administering to the animalan effective amount of a compound represented by any of defined FormulaeI-XXVI, or a pharmaceutically acceptable salt, prodrug or solvatethereof.

The present invention is further directed to a method of modulatingcalcium channels, especially N-type calcium channels, in an animal inneed thereof, said method comprising administering to the animal atleast one compound represented by any of defined Formulae I-XXVI, or apharmaceutically acceptable salt, prodrug or solvate thereof.

More specifically, the present invention provides a method of treating,preventing or ameliorating stroke, neuronal damage resulting from headtrauma, epilepsy, pain (e.g., acute pain or chronic pain, whichincludes, but is not limited to, neuropathic pain and inflammatorypain), migraine, a mood disorder, schizophrenia, a neurodegenerativedisorder (e.g., Alzheimer's disease, amyotrophic lateral sclerosis(ALS), or Parkinson's disease), depression, anxiety, a psychosis,hypertension, or cardiac arrhythmia. In one embodiment, the inventionprovides a method of treating pain. In another embodiment, the type ofpain treated is chronic pain. In another embodiment, the type of paintreated is neuropathic pain. In another embodiment, the type of paintreated is inflammatory pain. In another embodiment, the type of paintreated is acute pain. In each instance, such method of treatment,prevention, or amelioration requires administering to an animal in needof such treatment, prevention or amelioration an amount of a compound ofthe present invention that is therapeutically effective in achievingsaid treatment, prevention or amelioration. In one embodiment, theamount of such compound is the amount that is effective as to blockcalcium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 2000; 18: 387-391).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogenous disease state with an unclearetiology. In chronic neuropathic pain, the pain can be mediated bymultiple mechanisms. This type of pain generally arises from injury tothe peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic neuropathic painis different from acute pain in that patients suffer the abnormal painsensations that can be described as spontaneous pain, continuoussuperficial burning and/or deep aching pain. The pain can be evoked byheat-, cold-, and mechano-hyperalgesia or by heat-, cold-, ormechano-allodynia:

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiences. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XXVI, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament for treating, preventing or ameliorating a disorderresponsive to the blockade of calcium channels (e.g., any of thedisorders listed above) in an animal suffering from said disorder. Inone embodiment, the disorder is responsive to the selective blockade ofN-type calcium channels.

Furthermore, the present invention is directed to a method of modulatingcalcium channels, especially N-type calcium channels, in an animal inneed thereof, said method comprising administering to the animal atleast one compound represented by any of defined Formulae I-XXVI.

The present invention is also directed to the use of a compoundrepresented by any of defined Formulae I-XXVI, or a pharmaceuticallyacceptable salt, prodrug or solvate thereof, in the manufacture of amedicament, in particular a medicament for modulating calcium channels,especially N-type calcium channels, in an animal in need thereof.

Synthesis of Compounds

The compounds of the present invention may be prepared using methodsknown to those skilled in the art in view of this disclosure. Forexample, compounds of Formula I where Z is Z¹ and R³ and R⁴ are bothhydrogen can be prepared as shown in Scheme 1:

wherein R¹, R², R⁵-R⁸, A, B, and m are as defined above. The method ofScheme I can also be used for preparing any corresponding compounds ofFormulae I-IX where Z is Z¹.

Compounds of Formula I where Z is Z¹ and R³ and R⁴ together form ═O canbe prepared as shown in Scheme 2;

wherein R¹, R², R⁵-R⁸, A, B, and m are as defined above: In preparingany corresponding compounds of Formula I where Q¹ is CR²⁰R²⁴, where R²⁴is hydrogen, Q² is CR²¹R²² and Q³ is N, advantageously DMAP/EDCI in DMFis used as the reagent. The method of Scheme 2 can be also used forpreparing any corresponding compounds of Formulae I-IX where Z is Z¹.

Compounds of Formula I where Z is Z² and R³ and R⁴ are both hydrogen canbe prepared as shown in Scheme 3:

wherein R¹, R², D, and n are as described above and R¹⁶ and R¹⁷ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano,amino, aminoalkyl, alkylamino, and dialkylamino, or R¹⁶ and R¹⁷ inadjacent carbon atoms form a bridge —O—CH₂—O—. The method of Scheme 3can be also used for preparing any corresponding compounds of FormulaeI-IX where Z is Z².

Compounds of Formula I where Z is Z² and R³ and R⁴ together form ═O canbe synthesized as shown in Scheme 4:

wherein R¹, R², D, and n are as described above and R¹⁶ and R¹⁷ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano,amino, aminoalkyl, alkylamino, and dialkylamino, or R¹⁶ and R¹⁷ togetherform a bridge —O—CH₂—O—. The method of Scheme 4 can be also used forpreparing any corresponding compounds of Formulae I-IX where Z is Z²

Compounds of Formula I where Z is Z³ can be prepared, for example, asshown in Scheme 5:

wherein R¹ and R² are as described above and R¹⁸ and R¹⁹ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,and alkylcarbonylamino. The method of Scheme can be also used forpreparing corresponding compounds of any of Formulae I-IX where Z is Z³.

Compounds of Formula I-IX where Z is Z⁴ can be prepared, inter alia, byusing the method described in Example 10 below.

Compounds of Formula I-IX where Z is Z⁵ can be prepared using methodssimilar to those described in Schemes 4 and 5 above.

Testing of Compounds

Compounds of the present invention were assessed by calcium mobilizationand/or electrophysiological assays for calcium channel blocker activity.One aspect of the present invention is based on the use of the compoundsherein described as N-type calcium channel blockers. In one aspect ofthe present invention, it has been found that certain compounds hereindescribed show selectivity as N-type calcium, channel blockers. Basedupon this property, these compounds are considered useful in treating,preventing, or ameliorating stroke, neuronal damage resulting from headtrauma, migraine, epilepsy, a mood disorder, schizophrenia, aneurodegenerative disorder (such as, e.g., Alzheimer's disease, ALS, orParkinson's disease), a psychosis, depression, anxiety, hypertension, orcardiac arrhythmia. The compounds of the present invention are alsoconsidered to be effective in treating, preventing or ameliorating pain,such as acute pain, chronic pain, which includes but is not limited toneuropathic pain and inflammatory pain, or surgical pain.

More specifically, the present invention is directed to compounds ofFormulae I-XXVI that are blockers of calcium channels. According to thepresent invention, those compounds having preferred N-type calciumchannel blocking properties exhibit an IC₅₀ of about 100 μM or less inthe calcium mobilization and/or electrophysiological assays describedherein. Preferably, the compounds of the present invention exhibit anIC₅₀ of 10 μM or less. More preferably, the compounds of the presentinvention exhibit an IC₅₀ of about 6 M or less. Most preferably, thecompounds of the present invention exhibit an IC₅ so of about 1.0 μM orless. The compounds of the present invention can be tested for theirN-type and L-type Ca²⁺ channel blocking activity by the followingcalcium mobilization and/or electrophysiological assays.

In one embodiment, compounds useful in the present invention are thoserepresented by any one of Formulae I-XXVI that exhibit selectivity forN-type calcium channels over L-type calcium channels in the calciummobilization and/or electrophysiological assays described herein. Thephrase “selectivity for N-type calcium channels over L-type calciumchannels” is used herein to mean that the ratio of an IC₅₀ for L-typechannel blocking activity for a compound of the present invention overan IC₅₀ for N-type channel blocking activity for the same compound ismore than I, i.e., LTCC IC₅₀/NTCC IC₅₀>1. Preferably, compounds of thepresent invention exhibit an LTCC IC₅₀/NTCC IC₅₀ ratio of about 2 ormore, about 10 or more, about 20 or more, about 30 or more, about 50 ormore, or about 100 or more.

Calcium Mobilization and Electrophysiological Assay Protocols:

Cell maintenance and differentiation.

Unless noted otherwise, cell culture reagents were purchased fromMediatech of Herndon, Md. IMR32 cells (American Type Culture Collection,ATCC, Manassas, Va.) were routinely cultured in growth medium consistingof minimum essential medium containing 10% fetal bovine serum (FBS,Hyclone, Logan, Utah), 100 U/mL penicillin, 100 μg/mL streptomycin, 2 mML-glutamine, 1 mM sodium pyruvate, and 1×MEM non-essential amino acids.80-90% confluent flasks of cells were differentiated using the followingdifferentiation medium: Growth medium plus 1 mM dibutyryl cyclic AMP(Sigma, St. Louis, Mo.), and 2.5 μM bromodeoxyuridine (Sigma). Cellswere differentiated for 8 days by replacing differentiation medium every2-3 days.

A7r5 (ATCC) cells were maintained and routinely cultured in A7r5 growthmedium consisting of Dulbecco's Modified Eagles Medium containing 10%FBS, 100 U/mL penicillin, 100 μg/mL streptomycin, 4 mM L-glutamine, and0.15% sodium bicarbonate. 80-90% confluent flasks of cells weredifferentiated using the following differentiation medium: A7r5 GrowthMedium plus 1 mM dibutyryl cyclic AMP (Sigma). Cells were differentiatedfor 8 days by replacing differentiation medium every 2-3 days.

Recombinant human embryonal kidney cells (HEK293, ATCC) stably

transfected with either N-type calcium channel (NTCC) subunits (α1b,α28, and β3) or L-type calcium channel (LTCC) subunits (α1c, α2ι, and(β1) were routinely cultured in growth medium consisting of Dulbecco'sModified Eagles Medium containing 10% FBS, 100 U/mL penicillin, 100μg/mL streptomycin, 4 mM L-glutamine, 500 μg/mL geneticin (G418), 20μg/mL Blasticidin S (InVivogen, San Diego, Calif.) and 500 μg/mL zeocin(InVivogen).

FLIPR Calcium Mobilization Assay for N-type Calcium Channel.

One day prior to performing this assay, differentiated IMR32 cells weretreated with 1× CellStripper, and seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at200,000 cells/well. On the day of the assay, the cell plates were washedwith IMR32 buffer (127 mM NaCl, 1 mM KCl, 2 mM MgCl₂, 700 μM NaH₂ PO₄, 5mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), thenpre-stimulated with KCl and loaded as follows: 0.05 mL of IMR32 buffer,0.05 mL of each compound tested diluted in IMR32 buffer containing 20 μMnitrendipine (Sigma), and 0.1 mL KCl dissolved in IMR32 buffer, plusFluo-4 were added (3 μM final concentration, Molecular Probes, Eugene,Oreg.). Final test compound concentrations ranged from about 846 pM toabout 17 μM, final nitrendipine concentration was 5 μM, and final KClconcentration was 90 mM. After 1 hour, the cells were washed twice with0.05 mL of each compound tested in nitrendipine-containing IMR32 buffer(no KCl or Fluo-4), and then replaced with 0.1 mL of each compoundtested in nitrendipine-containing IMR32 buffer. Plates were thentransferred to a Fluorimetric Imaging Plate Reader (FLIPR⁹⁶, MolecularDevices, Inc., Sunnyvale, Calif.) for assay. The FLIPR measured basalFluo-4 fluorescence for 315 seconds (i.e., 5 minutes and 15 seconds),then added 0.1 mL KCl agonist dissolved in IMR32 buffer and measuredfluorescence for another 45 seconds. Final test compound concentrationson the cells after FLIPR read ranged from about 846 pM to about 17 μM,final nitrendipine concentration was 5 μM, and final KCl concentrationwas 90 mM. Data were collected over the entire time course and analyzedusing Excel, Graph Pad Prism (version 3.02, Graph Pad, San Diego,Calif.), or an in-house non-linear regression analysis software.

FLIPR Calcium Mobilization Assay for L-type Calcium Channel.

One day prior to performing this assay, HEK293 cells stably expressingrecombinant rat L-type calcium channel (LTCC) subunits (α1c, α2δ, andβ1) are trypsinized, then seeded on poly-D-lysine-coated 96-wellclear-bottom black plates (Becton Dickinson, Franklin Lakes, N.J.) at75,000 cells/well. On the day of the assay, the plates are washed withLTCC wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μM NaH₂PO₄, 5 mM CaCl₂, 5mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4), then loaded with 0.1 mLof LTCC wash buffer containing Fluo-4 (3 μM final concentration,Molecular Probes, Eugene, Oreg.). After 1 hour, the cells are washedwith 0.1 mL LTCC wash buffer and resuspended in 0.05 mL LTCC assaybuffer (same composition as LTCC wash buffer). Plates are thentransferred to a FLIPR⁹⁶ for assay. The FLIPR measures basal Fluo-4fluorescence for 15 seconds, then adds 0.05 mL of each compound testeddiluted in LTCC assay buffer at final concentrations ranging from about846 pM to about 17 μM. Fluo-4 fluorescence is then measured for 5minutes. 0.1 mL KCl agonist dissolved in LTCC assay buffer is then addedto the cells to produce a final concentration of 90 mM KCl, andfluorescence is measured for another 45 seconds. Data are collected overthe entire time course and analyzed using Excel, Graph Pad Prism, or anin-house regression analysis software.

Alternative FLIPR Calcium Mobilization Assay for L-type Calcium Channel.

Alternatively, the following cell line and procedure was used for theFLIPR calcium mobilization assay for L-type calcium channel. One dayprior to performing this assay, differentiated A7r5 cells weretrypsinized, then seeded on tissue culture treated 96-well clear-bottomblack plates (Becton Dickinson, Franklin Lakes, N.J.) at a dilution of1:1 from a confluent T150 cm² flask. On the day of the assay, the plateswere washed with A7r5 wash buffer (127 mM NaCl, 2 mM MgCl₂, 700 μMNaH₂PO₄, 5 mM CaCl₂, 5 mM NaHCO₃, 8 mM HEPES, 10 mM glucose, pH 7.4),then loaded with 0.1 mL of A7r5 wash buffer containing Fluo-4 (3 μMfinal concentration, Molecular Probes, Eugene, Oreg.). After 1 hour, thecells were washed with 0.1 mL A7r5 wash buffer and resuspended in 0.05mL A7r5 assay buffer that was composed of A7r5 wash buffer plus 50 μMvalinomycin (Sigma). Plates were then transferred to a FLIPR⁹⁶ forassay. The FLIPR measured basal Fluo-4 fluorescence for 15 seconds, thenadded 0.05 mL of each compound tested diluted in A7r5 assay buffer atfinal concentrations ranging from about 846 pM to about 17 μM. Fluo-4fluorescence was then measured for 5 minutes. 0.1 mL KCl agonistdissolved in A7r5 assay buffer is then added to the cells to produce afinal concentration of 90 mM KCl, and fluorescence was measured foranother 45 seconds. Data were collected over the entire time course andanalyzed using Excel, Graph Pad Prism, or an in-house regressionanalysis software.

Cloning of N- and L-Type Calcium Channel Subunit Open Reading FramecDNAs.

Five cDNAs encoding subunits of the rat N- or L-type calcium channelswere cloned by PCR amplification in order to reconstitute functionalchannels in a heterologous system. These were the alpha1b (α1b), beta1(β1), beta3 (β3), alpha2delta (α28), and alpha1c (α1c) subunit cDNAs.The alpha1 b subunit cDNA has been described by Dubel et al. in Proc.Natl. Acad. Sci. U.S.A 89: 5058-5062 (1992). The beta1 subunit cDNA hasbeen described by Pragnell et al. in FEBS Lett. 291: 253-258 (1991). Thebeta3 subunit cDNA has been described by Castellano et al. in J. Biol.Chem. 268: 12359-12366 (1993). The alpha2delta subunit cDNA has beendescribed by Kim et al. in Proc. Natl. Acad. Sci. U.S.A. 89: 3251-3255(1992). The alpha1c subunit cDNA has been described by Koch et al. in J.Biol. Chem. 265: 17786-17791 (1990).

The 7.0 kb cDNA containing the entire cab open reading frame (ORF) wasPCR amplified as two overlapping cDNA fragments, i.e., a 2.7 kb 5′fragment and a 4.4 kb 3′ fragment. The 5′ fragment was amplified fromrat brain cDNA using primers I (SEQ ID NO:1, TABLE 1) and 2 (SEQ IDNO:2, TABLE 1), and the 3′ fragment was amplified from rat spinal cordcDNA using primers 3 (SEQ ID NO:3, TABLE 1) and 4 (SEQ ID NO:4, TABLE1). The two fragments were joined by ligation at a common restrictionsite to create the entire 7.0 kb cDNA. This ORF encodes the proteinisoform generated by alternative splicing termed “+A ΔSFMG ΔET”according to the nomenclature of Lin et al. (Neuron 18: 153-166 (1997)).The entire cDNA was sequenced with redundant coverage on both strands.The cDNA was then inserted into the mammalian expression vectorpcDNA6.2DEST (Invitrogen, Carlsbad Calif.) by homologous recombinationusing the Gateway system (Invitrogen).

The 1.8 kb cDNA encoding the β1 subunit, the 1.45 cDNA encoding thebeta3 subunit, and the 3.3 kb cDNA encoding the alpha2delta subunit werecloned by PCR amplification from rat spinal cord cDNA (β1) or brain cDNA(β3, α2δ). Primers 5 (SEQ ID NO:5, TABLE 1) and 6 (SEQ ID NO:6, TABLE 1)were used for the β1 cDNA amplification; primers 7 (SEQ ID NO:7,TABLE 1) and 8 (SEQ ID NO:8, TABLE 1) were used for the (33 cDNAamplification; and primers 9 (SEQ ID NO:9, TABLE 1) and 10 (SEQ IDNO:10, TABLE 1) were used for the α2δ cDNA amplification. PCR productswere subcloned and fully sequenced on both strands. Clones matching thereference sequence (β1: NM 017346; (33: NM_(—)012828; α2δ: M86621) andthe gene's GenBank rat genomic DNA sequences were recombined into themammalian expression vector pcDNA3.2DEST (β1, β3) or pcDNA3.1-Zeo (α2δ),which had been modified to a vector compatible with the Gatewayrecombination system using the Gateway vector adaptor kit (Invitrogen).Proper recombination was confirmed by sequencing of recombinogenicregions. For (β3 expression vector, proper protein expression wasconfirmed by Western blot analysis of lysates of transfected HEK293cells using a rabbit polyclonal antiserum directed against the rat β3subunit (USA Biological).

The 6.5 kb cDNA encoding the L-type calcium channel α1c subunit wascloned by PCR amplification from rat heart cDNA using primers 11 (SEQ IDNO:11, TABLE 1) and 12 (SEQ ID NO:12, TABLE 1). The PCR fragment wassubcloned and fully sequenced on both strands to confirm its identity. Aclone matching consensus reference sequence M59786 and rat genomic DNAsequences was recombined into the mammalian expression vectorpcDNA6.2DEST. Sequences around the recombinogenic region were sequencedto confirm accurate recombination into the expression vector.

TABLE 1 PRIMER SEQUENCE SEQ ID NO CACC ATG GTC CGC TTC GGG GAC  1CCG TTC AGT GGC CTC CTC C  2 C TAG CAC CAG TGA TCC TGG TCTG  3AGT GCG TTG TGA GCG CAG TA  4 CAC CAT GGT CCA GAA GAG CGG  5TCTCAGCGGATGTAGACGCCT  6 CAC CAT GTA TGA CGA CTC CTA C  7GGT GGT CAG TAG CTG TCC TTA GG  8 CAC CAT GGC TGC TGG CTG CCT  9AGA GGG TCA CCA TAG ATA GTG TCT G 10 CACCATGATTCGGGCCTTCGCT 11AGCCTGCGGACTACAGGTTGCTGAC 12

N-Type Recombinant Cell Line Development.

N-type calcium channel expressing HEK-293 cells were created in twostages. Stage 1 was created as follows. The rat α1b, and β3 cDNAexpression constructs (2.5 μg each) were co-transfected into humanembryonic kidney (HEK-293) cells by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin and 500 μg/mL geneticin,and incubated for 3 weeks at 37° C., 5% CO₂, 95% humidity. Platescontaining ≦1 clone per well were cultured until wells positive forsingle clones were confluent. Individual clones were then arrayed intocolumns of a destination 96-well plate, and partly split into 6-wellplates for culture maintenance. Array plates were washed once with IMR32buffer and cells loaded for 1 hour with 0.1 mL of IMR32 buffercontaining Fluo-4 (3 μM final concentration, Molecular Probes). Thenthey were washed twice with 0.1 mL of IMR32 buffer, and replaced with0.1 mL IMR32 buffer. Plates were then transferred to a FLIPR⁹⁶ forassay. The FLIPR measured basal Fluo-4 fluorescence for 315 seconds,then added 0.1 mL KCl agonist dissolved in IMR32 buffer and measuredfluorescence for another 45 seconds. Final KCl concentration was 90 mM.Data were collected over the entire time course and analyzed usingExcel, Graph Pad Prism, or Activity Base (version 5.1, IDBS, Parsippany,N.J.) software. The clone with the greatest signal-to-noise ratio, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) was expanded, characterized and usedfor stage 2 cell line development.

Stage 2 of N-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 N-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise, beststability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded, characterized andtested in electrophysiology for the best current size, N-typepharmacology, N-type characteristic current-voltage relationship andkinetics as described below.

L-type Recombinant Cell Line Development.

L-type calcium channel expressing HEK-293 cells were created in twostages. Stage 1 was created as follows. The rat α1c, and β1 cDNAexpression constructs (2.5 μg each) were co-transfected into humanembryonic kidney (HEK-293) cells by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin and 500 μg/mL geneticin,and incubated for 3 weeks at 37° C., 5% CO₂, 95% humidity. Platescontaining ≦1 clone per well were cultured until wells positive forsingle clones were confluent. Individual clones were then arrayed intocolumns of a destination 96-well plate, and partly split into 6-wellplates for culture maintenance. Array plates were washed once with LTCCwash (or assay) buffer and cells loaded for 1 hour with 0.1 mL of LTCCbuffer containing Fluo-4 (3 μM final concentration, Molecular Probes).Then they were washed twice with 0.1 mL of LTCC buffer, and replacedwith 0.1 mL LTCC buffer. Plates were then transferred to a FLIPR⁹⁶ forassay. The FLIPR measured basal Fluo-4 fluorescence for 315 seconds,then added 0.1 mL KCl agonist dissolved in LTCC buffer and measuredfluorescence for another 45 seconds. Final KCl concentration was 90 mM.Data were collected over the entire time course and analyzed usingExcel, Graph Pad Prism, or Activity Base software. The clone with thegreatest signal-to-noise ratio, best stability of response with passagenumber, and best adhesion to PDL precoated plates (Becton Dickinson) wasexpanded, characterized and used for stage 2 cell line development.

Stage 2 of L-type cell line development was carried out as follows. Therat α2δ cDNA expression construct (5 μg each) was transfected into thestage 1 L-type clonal cell line by Lipofectamine Plus reagent(Invitrogen), as per manufacturer's instructions. 24 hours later, cellswere split in limiting dilution into multiple 96-well plates inselection media containing 20 μg/mL blasticidin, 500 μg/mL geneticin,and 250 μg/mL zeocin and incubated for 3 weeks at 37° C., 5% CO₂, 95%humidity. Plates containing≦1 clone per well were cultured and handledaccording to the same steps and procedures described above for the stage1 cell line. The three clones with the greatest signal-to-noise ratio,best stability of response with passage number, and best adhesion to PDLprecoated plates (Becton Dickinson) were expanded and characterized.

N-type Electrophysiology in Recombinant Cells.

For electrophysiological recording, the cells expressing α1b, β3 and α2δsubunits were seeded on 35-mm culture Petri dishes at a density ofapproximately 10⁴ cells/dish and kept in an incubator for up to threedays for subsequent recordings. For recordings, the dishes werepositioned on the stage of an inverted microscope (Nikon, Eclipse E600,Japan) superfused with a bath solution comprised of BaCl₂ (11 mM), MgCl₂(1.5 mM), HEPES (10 mM), TEA chloride (120 mM), glucose (10 mM) adjustedto pH 7.4 with KOH. Whole-cell voltage-clamp recordings were made usingconventional patch-clamp techniques (Hamill et al., Pfluegers Arch. 391:85-100 (1981)) at room temperature (22-24° C.). The patch-clamp pipetteswere pulled from WPI, thick-walled borosilicate glass (WPI, Sarasota,Fla.). Currents were recorded using an Axopatch 200 A amplifier (AxonInstruments, Union City, Calif.) and were leak-subtracted (P/4),low-pass filtered (1 kHz, 4-pole Bessel), digitized (20-50-μsintervals), and stored using Digidata 1200 B interface andPclamp8.0/Clampex software (Axon Instruments, Union City, Calif.). Thepipettes were back-filled with internal solution containing CsCl (110mM), MgCl₂ (3 mM), EGTA (3 mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂ GTP(0.5 mM), and adjusted to pH 7.2 with CsOH. The pipette resistanceranged from 2 to 3 MOhm and was compensated by 75-80% by the built-inelectronic circuitry.

Currents were elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 20 sec. At the −90 mV membrane voltage about 50% ofchannels were in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.Every drug was applied at 3 to 4 concentrations increasing in acumulative manner. Fractional inhibition levels in steady-state wereused to draw the partial inhibition concentration curves to get the IC₅₀(i.e. concentration causing 50% reduction in the size of the response)values at −90 mV.

Stock solutions of each test compound were prepared using DMSO. Serialdilutions to desired concentrations were done with bath solution;concentration of DMSO in final solutions was 0.1%. Drugs were applied bygravity flow using a plane multi-barrel array shooter positioned 0.5 mmapart from the cell.

All curve fittings were carried out using Origin software (version 5.0,Microcal). A Hill equation was fit to the concentration-inhibitioncurves to determine IC₅₀ values.

N-Type Electrophysiology in Neuronal Cells.

To determine dissociation constants in resting versus inactivated statefor N-type calcium channels, neuronal cells that endogenously expressN-type calcium channels can be used. For electrophysiological recording,the neuronal cells expressing N-type calcium channels are seeded on35-mm culture Petri dishes at a density of approximately 10⁴ cells/dishand kept in an incubator for up to three days for subsequent recordings.For recordings, the dishes are positioned on the stage of an invertedmicroscope (Nikon, Eclipse E600, Japan) and superfused with a bathsolution comprised of BaCl₂ (11 mM), MgCl₂ (1.5 mM), HEPES (10 mM), TEAchloride (120 mM), glucose (10 mM) adjusted to pH 7.4 with KOH.Whole-cell voltage-clamp recordings are made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391: 85-100(1981)) at room temperature (22-24° C.). The patch-clamp pipettes arepulled from WPI, thick-walled borosilicate glass (WPI, Sarasota, Fla.).Currents are recorded using an Axopatch 200 A amplifier (AxonInstruments, Union City, Calif.) and leak-subtracted (P/4), low-passfiltered (1 kHz, 4-pole Bessel), digitized (20-50-μs intervals), andstored using Digidata 1200 B interface and Pclamp8.0/Clampex software(Axon Instruments, Union City, Calif.). The pipettes are back-filledwith internal solution containing CsCl (110 mM), MgCl₂ (3 mM), EGTA (3mM), HEPES (40 mM), Mg-ATP (4 mM), Na₂ GTP (0.5 mM), and adjusted to pH7.2 with CsOH. The pipette resistance ranges from 2 to 3 MOhm and iscompensated by 75-80% by the built-in electronic circuitry.

Currents are elicited by stepping from a holding potential of −90 mV to0 mV for 20 ms every 10 sec. At the −90 mV membrane voltage a proportionof channels is in the inactivated state, and thus contact with a blockerwould involve interaction with both resting and inactivated channels.This protocol is used as a first tier screen. For dissection of twocomponents of inhibition (resting block with the apparent dissociationconstant K_(r) and inactivated state block with K_(i)), steady-stateinactivation curves are collected using a double-pulse protocol.Three-second long depolarizing pre-pulse incrementing in 10 mV steps isfollowed by a 10 ms test pulse to 0 mV.

Stock solutions of each test compound are prepared using DMSO. Serialdilutions to desired concentrations are done with bath solution;concentration of DMSO in final solutions is 0.1%. Drugs are applied bygravity flow using a plane multi-barrel array shooter positioned ˜1 mmapart from the cell.

All curve fittings can be carried out using Origin software (version5.0, Microcal). A Hill equation is used to fit theconcentration-response curves and to determine IC₅₀ values. A Boltzmanequation is used to fit inactivation curves, returning half-inactivationvoltage, V_(0.5), slope p and the amplitude of current at the mostnegative voltage where eventually all channels are in the resting state.These parameters are used to calculate the apparent dissociationconstants: K_(r)=((Ab/Ac)/(1−(Ab/Ac))[b]) where [b] is the drugconcentration, Ac is the maximum test current amplitude in controlconditions and Ab is the maximum test current amplitude in the presenceof a blocker; K_(i)=[b]/((exp(−(dx/p))*(1+([b]/K_(r)))−1) where dx isthe difference between half-inactivation voltage V_(0.5) in the presenceand absence of drug and p is the slope.

In Vivo Pharmacology

The compounds of the present invention can be tested for in vivoanticonvulsant activity after i.v., p.o., or i.p. injection using any ofa number of anticonvulsant tests in mice or rats, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and in maleSprague-Dawley rats weighing between 200-225 g by application of current(for mice: 50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration,D.C.; for rats: 99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 secduration, D.C.) using a Ugo Basile ECT device (Model 7801). Mice arerestrained by gripping the loose skin on their dorsal surface andsaline-coated corneal electrodes are held lightly against the twocorneae. Rats are allowed free movement on the bench top and ear-clipelectrodes are used. Current is applied and animals are observed for aperiod of up to 30 seconds for the occurrence of a tonic hindlimbextensor response, A tonic seizure is defined as a hindlimb extension inexcess of 90 degrees from the plane of the body. Results can be treatedin a quantal manner.

The compounds can be tested for their antinociceptive activity in theformalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole,J. Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice(20-30 g; Harlan, San Diego, Calif.) can be used in all experiments.Food is withdrawn on the day of experiment. Mice are placed inPlexiglass jars for at least 1 hour to acclimate to the environment.Following the acclimation period mice are weighed and given either thecompound of interest administered i.p. or p.o., or the appropriatevolume of vehicle (e.g., 10% Tween-80) as control. Fifteen minutes afterthe i.p. dosing, and minutes after the p.o. dosing mice are injectedwith formalin (20 L of 5% formaldehyde solution in saline) into thedorsal surface of the right hind paw. Mice are transferred to thePlexiglass jars and monitored for the amount of time spent licking orbiting the injected paw. Periods of licking and biting are recorded in5-minute intervals for 1 hour after the formalin injection. Allexperiments are done in a blinded manner during the light cycle. Theearly phase of the formalin response is measured as licking/bitingbetween 0-5 minutes, and the late phase is measured from 15-50 minutes.Differences between vehicle and drug treated groups can be analyzed byone-way analysis of variance (ANOVA). A P value<0.05 is consideredsignificant. Compounds are considered to be efficacious for treatingacute and chronic pain if they have activity in blocking both the earlyand second phase of formalin-induced paw-licking activity.

Compounds can be tested for their potential to treat chronic pain (i.e.,antiallodynic and antihyperalgesic activities) using the Chung model ofperipheral neuropathy (Kim and Chung, Pain 50: 355-363 (1992)). MaleSprague-Dawley rats weighing between 200-225 g are anesthetized withhalothane (1-3% in a mixture of 70% air and 30% oxygen), and their bodytemperature controlled during anesthesia through use of a homeothermicblanket. A 2-cm dorsal midline incision is then made at the L5 and L6level, and the para-vertebral muscle groups retracted bilaterally. L5and L6 spinal nerves are then exposed, isolated, and tightly ligatedwith 6-0 or 7-0 silk suture. A sham operation is performed exposing thecontralateral L5 and L6 spinal nerves, without ligating, as a negativecontrol.

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Sensitivity to noxious mechanical stimuli can be measured in animalsusing the paw pressure test to assess mechanical hyperalgesia. In rats,hind paw withdrawal thresholds (“PWT”), measured in grams, in responseto a noxious mechanical stimulus are determined using an analgesymeter(Model 7200, commercially available from Ugo Basile of Italy), asdescribed in Stein (Biochemistry & Behavior 31: 451-455 (1988)). Therat's paw is placed on a small platform, and weight is applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. In one non-limitingembodiment, mechanical hyperalgesia associated with nerve injury inducedpain (neuropathic pain) can be assessed in rats. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

Pharmaceutical Compositions

Although a compound of the present invention may be administered to amammal in the form of a raw chemical without any other componentspresent, the compound is preferably administered as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Compositions within the scope of the present invention include allcompositions where a compound of the present invention is combined witha pharmaceutically acceptable carrier. In a preferred embodiment, thecompound is present in the composition in an amount that is effective toachieve its intended therapeutic purpose. While individual needs mayvary, a determination of optimal ranges of effective amounts of eachcompound is within the skill of the art. Typically, the compounds may beadministered to mammal, e.g. human, orally at a dose of from about0.0025 to about 1500 mg per kg body weight of the mammal, or anequivalent amount of a pharmaceutically acceptable salt, prodrug orsolvate thereof, per day to treat the particular disorder. A useful oraldose of a compound of the present invention administered to a mammal isfrom about 0.0025 to about 50 mg per kg body weight of the mammal, or anequivalent amount of the pharmaceutically acceptable salt, prodrug orsolvate thereof. For intramuscular injection, the dose is typicallyabout one-half of the oral dose.

A unit oral dose may comprise from about 0.01 to about 50 mg, andpreferably about 0.1 to about 10 mg, of the compound. The unit dose canbe administered one or more times daily as one or more tablets, eachcontaining from about 0.01 to about 50 mg of the compound, or anequivalent amount of a pharmaceutically acceptable salt or solvatethereof.

A pharmaceutical composition of the present invention can beadministered to any animal that may experience the beneficial effects ofa compound of the present invention. Foremost among such animals aremammals, e.g., humans and companion animals, although the invention isnot intended to be so limited.

A pharmaceutical composition of the present invention can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, health, and weight of the recipient,condition or disorder to be treated, kind of concurrent treatment, ifany, frequency of treatment, and the nature of the effect desired.

In one embodiment, a pharmaceutical composition of the present inventioncan be administered orally and is formulated into tablets, dragees,capsules or an oral liquid preparation. In one embodiment, the oralformulation comprises extruded multiparticulates comprising the compoundof the invention.

Alternatively, a pharmaceutical composition of the present invention canbe administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present invention canbe administered by injection.

Alternatively, a pharmaceutical composition of the present invention canbe administered transdermally.

Alternatively, a pharmaceutical composition of the present invention canbe administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present invention canbe administered by the intravaginal route.

A pharmaceutical composition of the present invention can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present invention, such as a method for treating,preventing, or ameliorating a disorder responsive to the blockade ofcalcium channels in an animal in need thereof, can further compriseadministering a second therapeutic agent to the animal in combinationwith a compound of the present invention. In one embodiment, the othertherapeutic agent is administered in an effective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

A compound of the present invention (i.e., the first therapeutic agent)and the other therapeutic agent can act additively or, in oneembodiment, synergistically. In one embodiment, a compound of thepresent invention is administered concurrently with a second therapeuticagent; for example, a single composition comprising an effective amountof a compound of Formulae I-XXVI, and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentinvention further provides a pharmaceutical composition comprising acombination of a compound of the present invention, the secondtherapeutic agent, and a pharmaceutically acceptable carrier.Alternatively, a first pharmaceutical composition comprising aneffective amount of a compound of any of Formulae I-XXVI and a secondpharmaceutical composition comprising an effective amount of the secondtherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a compound of the present inventionis administered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, the compoundof the present invention is administered while the second therapeuticagent exerts its therapeutic effect, or the second therapeutic agent isadministered while the compound of the present invention exerts itspreventive or therapeutic effect for treating, preventing, orameliorating a disorder or condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, a β-adrenergicblocker, an anticonvulsant, an antidepressant, an anticancer agent, anagent for treating addictive disorder, an agent for treating Parkinson'sdisease and parkinsonism, an agent for treating anxiety, an agent fortreating epilepsy, an agent for treating a seizure, an agent fortreating a stroke, an agent for treating a pruritic condition, an agentfor treating psychosis, an agent for treating ALS, an agent for treatinga cognitive disorder, an agent for treating a migraine, an agent fortreating vomiting, an agent for treating dyskinesia, or an agent fortreating depression, or a mixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof.Examples of other suitable non-opioid analgesics include the following,non limiting, chemical classes of analgesic, antipyretic, nonsteroidalantiinflammatory drugs; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; paraaminophennol derivatives including acetaminophen and phenacetin; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic Antipyretic andAntiinflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties. Suitable Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocomine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, and cisplatin.

Therapeutic agents useful for treating or preventing an addictivedisorder include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, or a serotonin antagonist.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy or seizure include, but are not limited to, carbamazepine,ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin,primidone, valproic acid, trimethadione, benzodiazepines, gamma-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below; menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT3 receptor antagonistssuch as odansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazine, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A pharmaceutical composition of the present invention is preferablymanufactured in a manner which is itself known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid, or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate can be used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which may bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound may be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such asuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions and methods of the present invention. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the invention.

EXAMPLES Example 11-(4,4-Bis(4-fluorophenyl)butyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](10)

a) To a solution of 25.0 g (209.8 mmol) of the pyridine compound 1 in200 mL of dichloromethane (DCM) at 0° C. was added m-chloroperbenzoicacid (m-CPBA) portionwise. The resulting mixture was stirred at 0° C.for 2 hours, warmed to room temperature and stirred for an additional 7hours. After this period, a saturated solution of 50 mL of aqueousNa₂S₂O₃ was added and the mixture was stirred for 0.5 hour. A saturatedsolution of 50 mL of aqueous NaHCO₃ was added slowly to this mixture.The layers were separated, and the aqueous layer was extracted with 500mL of DCM. The organic layers were combined and washed with 100 mL ofbrine solution and dried with anhydrous Na₂SO₄. The organic layer wasthen concentrated to give 21.3 g of the N-oxide 2 as a white solid.

b) A 20 g portion of the N-oxide 2 was dissolved in 161.5 mL of aceticanhydride/water solution (99:1). The resulting pink solution was stirredat room temperature for 10 hours and then heated to 100° C. for 3.5hours. After this period, the reaction mixture was cooled to roomtemperature and the acetate 3 was isolated from the crude mixture byusing vacuum distillation (16.2 g).

c) Concentrated sulfuric acid (12.0 mL) was added portionwise withvigorous stirring to 10.2 g of acetate 3 at room temperature. After theaddition was complete, the reaction mixture was heated to 125° C. for 2hours. The reaction mixture was then cooled to room temperature andpoured into 100 g of ice. A 50 g portion of 50% aqueous NaOH solutionwas added slowly to the reaction mixture. The aqueous layer wasextracted with 100 mL of ether three times. The organic layer was driedover K₂CO₃ and concentrated to give 6.2 g of compound 4 as an orangeoil.

d) To a stirred solution of the pyridyl compound 4 (6.0 g, 51.22 mmol)in THF (25 mL) at 0° C. was added 102.44 mL (102.44 mmol) of LiHMDS (5).The resulting mixture was stirred at 0° C. for 1 hour and transferredvia cannula to a THF (50 mL) solution of compound 6 at 0° C. Theresulting reaction mixture was stirred at 0° C. for 1 hour and at roomtemperature for 12 hours. The solvent was removed by rotary evaporatorand the residue was purified by flash chromatography using a gradient ofethyl acetate/hexane as eluent to give 3.2 g of the BOG-protectedspirocycle 7. MS: m/z 287. ¹H NMR (400 MHz, CDCl₃): δ 8.38-8.33 (m, 1H),7.59-7.54 (m, 1H), 7.17-7.11 (m, 1H), 6.89-6.75 (m, 2H), 4.34-4.12 (m,2H), 3.33-3.17 (m, 2H), 2.15-2.04 (m, 2H), 1.49 (s, 9H), 1.42-1.31 (m,2H).

e)1-(4,4-Bis(4-fluorophenyl)butyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](10):5 mL of 2M HCl in ether (Aldrich) was added to the BOC protectedspirocycle 7 (0.62 g, 2.17 mmol) dissolved in 3 mL of DCM. The resultingmixture was stirred at room temperature for 10 hours and the volatileswere, removed by flushing with nitrogen gas followed by rotaryevaporator to give the spirocycle 8, that was redissolved in 6.0 mL ofDMF. 0.6 mL (4.34 mmol) of triethylamine and 0.73 g (2.59 mmol) of thealkyl chloride 9 (Across) were added to the DMF solution of the compound8 at room temperature. The resulting mixture was stirred at 85° C. for10 hours. The solvent was removed by Genevac®, and the resulting crudesample was purified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 0.2 g of the title compound 10. MS: m/z430.

¹H NMR (400 MHz, CDCl₃): δ 8.27-8.22 (m, 1H), 7.58-7.53 (m, 1H),7.19-7.08 (m, 5H), 6.99-6.91 (m, 4H), 6.87 (s, 2H), 6.75-6.70 (m, 1H),6.50-6.43 (m, 1H), 3.94-3.77 (m, 3H), 3.63-3.42 (br s, 2H), 3.27-3.15(m, 2H), 2.61-2.39 (br s, 2H), 2.16-2.04 (m, 2H), 1.84-1.72 (m, 2H),1.70-1.47 (br s, 2H).

Example 21,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one(12)

To a DMF (3.0 mL) solution of 0.4 g (1.97 mmol) of the spirocycle 11(Arch corporation) at room temperature was added 0.4 g (1.97 mmol) ofthe alkyl chloride 9 (Across) and 0.6 mL (5.9 mmol) of triethyl amine.The resulting mixture was stirred at 85° C. for 10 hours. The solventwas removed by Genevac® and the resulting crude sample was purified bycolumn chromatography using a gradient of ethyl acetate/hexane as eluentto give 90 mg of the title compound 12. MS: m/z 447. ¹H NMR (400 MHz,DMSO): δ 7.84-7.67 (m, 3H), 7.61-7.52 (m, 1H), 7.39-7.26 (s, 4H),7.16-7.02 (m, 4H), 6.57 (s, 1H), 4.04-3.93 (m, 1H), 2.88-2.75 (m, 2H),2.52-2.35 (m, 5H), 2.32-2.11 (m, 4H), 2.07-1.93 (m, 2H), 1.62-1.50 (m,2H), 1.42-1.27

Example 31,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one(14)

To a DCM (5.0 mL) solution of 0.1 g (0.42 mmol) of the spirocycle 11(Arch corporation) at room temperature was added 0.12 g (0.42 mmol) ofthe acid 13 (prepared as described in Collec. Czech. Chem. Comm. 38,1973, 3879-3901) followed by 57 mg (0.42 mmol) of 1-hydroxybenzotriazole(HOBT) and 88 mg (0.46 mmol) of N-ethyl-dimethylaminopropyl carbodiimidehydrochloride (EDCI). The resulting reaction mixture was stirred at roomtemperature for 3 hours and the volatiles were removed by usingGenevac®. The resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive mg of the title compound 14. MS: m/z 461. ¹H NMR (400 MHz, CDCl₃):δ 7.93-7.87 (m, 1H), 7.73-7.65 (m, 1H), 7.59-7.51 (m, 1H), 7.35-7.31 (m,1H), 7.24-7.16 (m, 4H), 7.03-6.92 (m, 4H), 4.81-4.67 (m, 1H), 4.03-3.95(m, 1H), 3.76-3.68 (m, 1H), 3.54-3.43 (m, 1H), 3.12-3.01 (m, 1H),2.45-2.23 (m, 4H), 2.08-1.86 (m, 2H), 1.78-1.64 (m, 2H).

Example 41-(4,4-bis(4-fluorophenyl)butanoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](15)

To a DMF (5.0 mL) solution of 0.08 g (0.43 mmol) of the spirocycle 8 atroom temperature was added 0.12 g (0.43 mmol) of the acid 13 (preparedas described in Collec. Czech. Chem. Comm. 38, 1973, 3879-3901) followedby 0.11 g (0.86 m mol) of 4-dimethylaminopyridine (DMAP) and 0.17 g(0.86 mmol) of EDCI. The resulting reaction mixture was stirred at roomtemperature for 48 hours and the volatiles were removed by usingGenevac®. The resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 50 mg of the title compound 15. MS: m/z 444. ¹H NMR (400 MHz,CDCl₃): δ 8.35-8.31 (m, 1H), 7.58-7.52 (m, 1H), 7.24-7.17 (m, 4H),7.16-7.10 (m, 1H), 7.02-6.94 (m, 4H), 6.82-6.74 (m, 2H), 4.57-4.48 (m,1H), 4.04-3.95 (m, 1H), 3.95-3.87 (m, 1H), 3.40-3.26 (m, 2H), 2.45-2.34(m, 2H), 2.34-2.25 (m, 2H), 2.04-1.91 (m, 2H), 1.51-1.35 (m, 2H).

Example 51-(4,4-bis(4-fluorophenyl)but-3-enoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](17)

To a DMF (10 mL) solution of 0.14 g (0.73 mmol) of the spirocycle 8 atroom temperature was added 0.2 g (0.73 mmol) of the acid 16 (prepared asdescribed in Collec. Czech. Chem. Comm. 38, 1973, 3879-3901) followed by0.19 g (1.46 mmol) of DMAP and 0.21 g (1.10 mmol) of EDCI. The resultingreaction mixture was stirred at room temperature for 12 hours and thevolatiles were removed by using Genevac®. The resulting crude sample waspurified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 0.30 g of the title compound 17. MS:m/z 442. ¹H NMR (400 MHz, CDCl₃): δ 8.35-8.32 (m, 1H), 7.59-7.54 (m,1H), 7.26-7.05 (m, 7H), 7.01-6.92 (m, 2H), 6.82-6.74 (m, 2H), 6.33-6.26(m, 1H), 4.56-4.44 (m, 1H), 3.95-3.84 (m, 1H), 3.46-3.28 (m, 2H),3.27-3.18 (m, 2H), 2.07-1.89 (m, 2H), 1.55-1.37 (m, 2H).

Example 61-(4-methoxybenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](19)

To a DMF (12.0 mL) solution of 0.20 g (1.1 mmol) of the spirocycle 8 atroom temperature was added 0.17 g (1.1 mmol) of the alkyl chloride 18(Aldrich) and 0.37 mL (2.15 mmol) of diisopropylethylamine (DIEA). Theresulting mixture was stirred at 80° C. for 12 hours. The solvent wasremoved by Genevac® and the resulting crude sample was purified bycolumn chromatography using a gradient of ethyl acetate/hexane as eluentto give 0.1 g the title compound 19. MS: m/z 306. ¹H NMR (CDCl₃): δ8.38-8.33 (m, 1H), 7.54-7.49 (m, 1H), 7.34-7.28 (m, 2H), 7.12-7.06 (m,1H), 6.95-6.89 (m, 1H), 6.89-6.83 (m, 2H), 6.76-6.71 (m, 1H), 3.79 (s,3H), 3.58 (s, 2H), 3.05-2.98 (m, 2H), 2.41-2.29 (m, 4H), 1.35-1.23 (m,2H).

Example 71-(4-isopropylbenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](21)

To a DMF (12.0 mL) solution of 0.20 g (1.1 mmol) of the spirocycle 8 atroom temperature was added 0.23 g (1.1 mmol) of the alkyl bromide 20(Aldrich) and 0.37 mL (2.15 mmol) of DIEA. The resulting mixture wasstirred at 80° C. for 12 hours. The solvent was removed by Genevac® andthe resulting crude sample was purified by column chromatography using agradient of ethyl acetate/hexane as eluent to give 20 mg of the titlecompound 21. MS: m/z 318. ¹H NMR (CDCl₃): δ 8.40-8.33 (m, 1H), 7.57-7.50(m, 1H), 7.36-7.28 (m, 2H), 7.22-7.15 (m, 2H), 7.14-7.07 (m, 1H),6.97-6.91 (m, 1H), 6.78-6.72 (m, 1H), 3.62 (s, 2H), 3.09-3.00 (m, 2H),2.96-2.85 (m, 1H), 2.45-2.30 (m, 4H), 1.35-1.20 (m, 8H).

Example 81-(4-dimethylaminobenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](23)

To a DCM (12.0 mL) solution of 99 mg (0.54 mmol) of the spirocycle 8 atroom temperature was added 98 mg (0.54 mmol) of the acid chloride 22(Aldrich) and 0.14 ml (0.81 mmol) of DIEA. The resulting mixture wasstirred at room temperature for 4 hours. The solvent was removed byGenevac® and the resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 18.0 mg of the title compound 23. MS: m/z 333. ¹H NMR (CDCl₃): δ8.39-8.34 (m, 1H), 7.60-7.55 (m, 1H), 7.46-7.41 (m, 2H), 7.18-7.12 (m,1H), 6.89-6.79 (m, 2H), 6.72-6.65 (m, 2H), 4.42 (s, 2H), 3.55-3.42 (m,2H), 2.99 (s, 6H), 2.19-2.09 (m, 2H), 1.54-1.44 (m, 2H).

Example 91-(4-trifluoromethylphenylsulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](25)

To a DCM (12.0 mL) solution of 99 mg (0.54 mmol) of the spirocycle 8 atroom temperature was added 132 mg (0.54 mmol) of the sulfonyl chloride24 (Aldrich) and 0.14 mL (0.81 mmol) of DIEA. The resulting mixture wasstirred at room temperature for 12 hours. The solvent was removed byGenevac® and the resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 30.0 mg of the title compound 25. MS: m/z 394. ¹H NMR (CDCl₃): δ8.25-8.19 (m, 1H), 8.02-7.94 (m, 2H), 7.89-7.82 (m, 2H), 7.56-7.50 (m,1H), 7.14-7.07 (m, 1H), 6.77-6.71 (m, 1H), 6.56-6.50 (m, 1H), 3.92-3.82(m, 2H), 3.17-3.07 (m, 2H), 2.12-2.01 (m, 2H), 1.72-1.61 (m, 2H).

Example 101-(4-methyl-2-methylaminopentanoyll)-spiro[piperidine-4,5′-cyclopenta[b]pyridine](28)

To a DMF (5.0 mL) solution of 0.5 g (2.69 mmol) of the spirocycle 8 atroom temperature was added 0.66 g (2.69 mmol) of the acid 26 followed by0.68 g (5.38 mmol) of DMAP and 1.03 g (5.38 mmol) of EDCI. The resultingreaction mixture was stirred at room temperature for 48 hours and thenthe volatiles were removed by using Genevac®. The resulting crude samplewas purified by column chromatography using a gradient of ethylacetate/hexane as eluent to give the compound 27 that was dissolved in asolution of 5 mL of trifluoroacetic acid and 15 mL of DCM. The resultingmixture was stirred at room temperature for 2 hours and then thevolatiles were removed by using Genevac®. The resulting crude sample waspurified by column chromatography using a gradient of ethylacetate/hexane as eluent to give the title compound 28. MS: m/z 313. ¹HNMR (CDCl₃): δ 8.37-8.32 (m, 1H), 7.61-7.55 (m, 1H), 7.19-7.13 (m, 1H),6.85-6.73 (m, 2H), 4.65-4.44 (m, 1H), 4.26-4.12 (m, 1H), 3.63-3.37 (m,3H), 2:46-2.30 (m, 4H), 2.15-1.81 (m, 3H), 1.65-1.29 (m, 4H), 0.99-0.75(m, 6H).

Example 111-[4,4-Bis(4-fluorophenyl)butyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](31)

a)1-Tert-butoxycarbonyl-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](29):To the BOC-protected spirocycle 7 (0.35 g, 1.22 mmol) dissolved in 10 mLof methanol under nitrogen atmosphere was added 41 mg ofpalladium/Charcoal (5%, Aldrich). The nitrogen atmosphere was replacedwith hydrogen gas. The resulting mixture was stirred at room temperaturefor 6 hours and then filtered through a pad of celite. The methanolsolution (200 mL) was concentrated and the resulting residue waspurified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 0.35 g of compound 29. MS: m/z 289. ¹HNMR (CDCl₃): δ 8.45-8.36 (m, 1H), 7.56-7.48 (m, 1H), 7.11-6.94 (m, 1H),4.28-3.99 (m, 2H), 3.19-2.82 (m, 4H), 2.23-1.88 (m, 4H), 1.47 (s, 9H).

b)1-[4,4-Bis(4-fluorophenyl)butyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](31):To 0.32 g (1.10 mmol) of1-tert-butoxycarbonyl-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](29)in 3 mL of DCM was added 5 mL of 2M HCl in ether (Aldrich). Theresulting mixture was stirred at room temperature for 10 hours and thenthe volatiles were removed by flushing with nitrogen gas followed byevaporation by rotary evaporator to give the unprotected spirocycle 30that was redissolved in 6.0 mL of DMF. To the DMF solution of compound30 at room temperature was added 0.3 mL (2.44 mmol) of triethylamine and0.34 g (1.22 mmol) of the alkyl chloride 9 (Across). The resultingmixture was stirred at 85° C. for 10 hours. The solvent was removed byGenevac® and the resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 50 mg of the title compound 31. MS: m/z 432. ¹H NMR (CDCl₃): δ8.34-8.20 (m, 1H), 7.52-7.43 (m, 1H), 7.17-7.11 (m, 4H), 7.10-7.05 (m,11H), 6.98-6.91 (m, 4H), 6.85 (s, 1H), 3.91-3.82 (m, 1H), 3.67-3.56 (m,2H), 3.32 (br s, 2H), 3.09 (br s, 3H), 2.88 (s, 3H), 2.13-1.97 (m, 9H),1.70 (s, 2H).

Example 121-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene](33)

To a DMF solution of 0.4 g (2.20 mmol) of the spiroindene 32 (Archcorporation) at room temperature was added 0.6 g (2.20 mmol) of the acid16 (prepared as described in Collec. Czech. Chem. Comm. 38, 1973,3879-3901) followed by 0.3 g (2.20 mmol) of HOBT and 0.46 g (2.4 mmol)of EDCI. The resulting reaction mixture was stirred at room temperaturefor 6 hours and the volatiles were removed by using Genevac®. Theresulting crude sample was purified by column chromatography using agradient of ethyl acetate/hexane as eluent to give 0.82 g of the titlecompound 33. MS: m/z 441. ¹H NMR (CDCl₃): δ 7.35-7.31 (m, 1H), 7.29-7.27(m, 1H), 7.45-7.15 (m, 5H), 7.12-7.05 (m, 2H), 7.01-6.94 (m, 2H),6.83-6.79 (m, 2H), 6.33-6.28 (m, 1H), 4.73-4.62 (m, 1H), 3.76-3.66 (m,1H), 3.34-3.18 (m, 3H), 3.07-2.95 (m, 1H), 2.06-1.85 (m, 2H), 1.44-1.26(m, 2H).

Example 131-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indene](34)

To a DMF (5.0 mL) solution of 0.2 g (1.1 mmol) of the spiroindene 32(Arch corporation) at room temperature was added 0.3 g (1.1 mmol) of theacid 13 (prepared as described in Collec. Czech. Chem. Comm. 38, 1973,3879-3901) followed by 0.15 g (1.1 mmol) of HOBT and 0.21 g (1.1 mmol)of EDCI. The resulting reaction mixture was stirred at room temperaturefor 6 hours and then the volatiles were removed by using Genevac®. Theresulting crude sample was purified by column chromatography using agradient of ethyl acetate/hexane as eluent to give 0.1 g of the titlecompound 34. MS: m/z 443. ¹H NMR (CDCl₃): δ 7.35-7.32 (m, 1H), 7.29-7.24(m, 1H), 7.24-7.18 (m, 5H), 7.02-6.95 (m, 4H), 6.83-6.79 (m, 2H),4.72-4.62 (m, 1H), 4.05-3.94 (m, 1H), 3.81-3.71 (m, 1H), 3.33-3.21 (m,1H), 3.05-2.91 (m, 1H), 2.48-2.26 (m, 3H), 2.04-1.82 (m, 2H), 1.43-1.28(m, 2H).

Example 141-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indane](35)

0.50 g (1.13 mmol) of1-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene](33)was dissolved in 20 mL of methanol under nitrogen atmosphere and then200 mg of palladium/Charcoal (5%, Aldrich) was added. The nitrogenatmosphere was replaced with hydrogen gas. The resulting mixture wasstirred at room temperature for 6 hours and filtered through a pad ofcelite. The methanol solution (200 mL) was concentrated and theresulting residue purified by column chromatography using a gradient ofethyl acetate/hexane as eluent to give 0.5 g of the title compound 35.MS: m/z 445. ¹H NMR (CDCl₃): δ 7.24-7.17 (m, 7H), 7.10-7.07 (m, 1H),7.02-6.95 (m, 4H), 4.67-4.57 (m, 1H), 4.04-3.93 (m, 1H), 3.68-3.58 (m,1H), 3.18-3.06 (m, 1H), 2.98-2.85 (m, 2H), 2.82-2.7.1 (m, 1H), 2.44-2.33(m, 2H), 2.33-2.24 (m, 2H), 2.14-1.99 (m, 2H), 1.82-1.61 (m, 2H),1.61-1.48 (m, 3H).

Example 151-[4,4-bis(4-fluorophenyl)butanoyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](36)

To a DMF (5.0 mL) solution of 0.29 g (1.25 mmol) of the compound 30 atroom temperature was added 0.2 g (1.25 mmol) of the acid 13 (prepared asdescribed in Collec. Czech. Chem. Comm. 38, 1973, 3879-3901) followed by0.18 g (1.45 mmol) of DMAP and 0.28 g (1.45 mmol) of EDCI. The resultingreaction mixture was stirred at room temperature for 10 hours and thenthe volatiles were removed by using Genevac®. The resulting crude samplewas purified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 40 mg of the title compound 36. MS: m/z446. ¹H NMR (CDCl₃): δ 8.39-8.35 (m, 1H), 7.52-7.46 (m, 1H), 7.23-7.14(m, 4H), 7.09-7.02 (m, 1H), 7.02-6.93 (m, 4H), 4.55-4.45 (m, 1H),4.02-3.93 (m, 1H), 3.78-3.67 (m, 1H), 3.21-3.08 (m, 1H), 3.05-2.94 (m,1H), 2.94-2.84 (m, 2H), 2.41-2.31 (m, 2H), 2.30-2.22 (m, 2H), 2.19-2.09(m, 1H), 2.07-1.86 (m, 3H), 1.55-1.43 (m, 2H).

Example 16 1-(4-methoxybenzyl)-spiro[piperidine-4,1′-indene](37)

To a DMF (5.0 mL) solution of 0.10 g (0.45 mmol) of the spirocycle 32(Arch Corporation) at room temperature was added 0.085 g (0.54 mmol) ofthe alkyl chloride 18 (Aldrich) and 0.12 mL (1.1 mmol) of triethylamine.The resulting mixture was stirred at 80° C. for 12 hours. The solventwas removed by Genevac® and the resulting crude sample was purified bycolumn chromatography using a gradient of ethyl acetate/hexane as eluentto give 31 mg of the title compound 37. MS: m/z 305. ¹H NMR (CDCl₃): δ7.40-7.37 (d, 1H), 7.32-7.28 (m, 3H), 7.25-7.16 (m, 2H), 6.91-6.83 (m,3H), 6.75-6.72 (m, 2H), 3.82 (s, 3H), 3.59 (s, 2H), 3.01-2.94 (m, 2H),2.39-2.30 (m, 2H), 2.24-2.14 (m, 2H), 1.39-1.30 (m, 2H).

Example 171-(4-iso-propylbenzyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](38)

To a DMF (7.0 mL) solution of 0.30 g (1.33 mmol) of the spirocycle 30 atroom temperature was added 0.28 g (1.33 mmol) of the alkyl bromide 20(Aldrich) and 0.42 mL (2.99 mmol) of triethylamine. The resultingmixture was stirred at 80° C. for 12 hours. The solvent was removed byGenevac® and the resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 50 mg of the title compound 38. MS: m/z 320. ¹H NMR (CDCl₃): δ8.43-8.37 (m, 1H), 7.50-7.45 (m, 1H), 7.35-7.27 (m, 2H), 7.20-7.15 (m,2H), 7.05-7.01 (m, 1H), 3.54 (s, 2H), 2.95-2.82 (m, 5H), 2.27-2.11 (m,4H), 2.09-2.01 (m, 2H), 1.52-1.41 (m, 2H), 1.29-1.20 (m, 6H).

Example 181-(3-trifluoromethyl-4-methoxyphenyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine](40)

To a DMF (7.0 mL) solution of 0.30 g (1.33 mmol) of the spirocycle 30 atroom temperature was added 0.36 g (1.33 mmol) of the alkyl bromide 39(Matrix Scientific) and 0.42 mL (2.99 mmol) of triethylamine. Theresulting mixture was stirred at 80° C. for 12 hours. The solvent wasremoved by Genevac® and the resulting crude sample was purified bycolumn chromatography using a gradient of ethyl acetate/hexane as eluentto give 80 mg of the title compound 40. MS: m/z 376. ¹H NMR (CDCl₃): δ8.43-8.38 (m, 1H), 7.56-7.45 (m, 3H), 7.06-7.00 (m, 1H), 6.98-6.93 (m,1H), 3.90 (s, 3H), 3.51 (s, 2H), 2.90-2.82 (m, 4H), 2.25-2.10 (m, 4H),2.09-2.02 (m, 2H), 1.50-1.43 (m, 2H).

Example 191,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isobenzofuran-1,4′-piperidine(42)

To a DMF (10.0 mL) solution of 0.25 g (1.1 mmol) of the spirocycle 41(Arch corporation) at room temperature was added 0.31 g (1.1 mmol) ofthe alkyl chloride 9 (Across) and 0.29 mL (1.65 mmol) ofdiisopropylethyl amine. The resulting mixture was stirred at 80° C. for10 hours. The solvent was removed by Genevac® and the resulting crudesample was purified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 40 mg of the title compound 42. MS: m/z433. ¹H NMR (CDCl₃): δ 7.34-7.27 (m, 3H), 7.23-7.15 (m, 5H), 7.02-6.95(m, 4H), 5.06 (s, 2H), 3.97-3.89 (m, 1H), 3.40-3.29 (m, 2H), 3.10-2.99(m, 2H), 2.99-2.91 (m, 2H), 2.79-2.65 (m, 2H), 2.16-2.05 (m, 2H),1.92-1.77 (m, 4H).

Example 202-Benzyl-2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isoindole-1,4′-piperidine]-3-one(51)

a) To a solution of 1.1 g (5.6 mmol) of1-tert-butoxycarbonyl-4-piperidone 43 in 20 mL of toluene at roomtemperature was added 0.6 g (5.57 mmol) of benzyl amine 44. Theresulting mixture was stirred at 80° C. for 3 hours and then thevolatiles removed. The resulting crude sample was redissolved in 30 mLof toluene and acid chloride 46 (1.13 g, 4.24 mmol) was added to themixture followed by 0.96 mL (6.9 mmol) of triethylamine. The resultingreaction mixture was stirred at 80° C. for 12 hours. The mixture wascooled to room temperature and diluted with 100 mL of ethyl acetate.This solution was washed with aqueous NaHCO₃. The layers were separatedand the organic layer was dried (Na₂SO₄) and then concentrated to give acrude sample that was purified by column chromatography using a gradientof ethyl acetate/hexane as eluent to give 1.6 g of the compound 47.

b) A 3.0 g portion of compound 47 was dissolved in 10 mL of acetonitrileand 260 mg (1.16 mmol) of Pd(OAc)₂, 243 mg (0.93 mmol) of PPh₃, 1.28 g(9.7 mmol) K₂ CO₃, and 1.86 g (5.79 mmol) were added to it. The mixturewas stirred at 80° C. for 12 hours and then the volatiles were removedby using Genevac®. The resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 1.1 g of compound 48.

c) To a stirred solution of compound 48 (1.1 g, 2.82 mmol) in MeOH (40mL) at room temperature under nitrogen was added 0.4 g of Pd(OH)₂ onCarbon. The nitrogen gas was replaced with hydrogen gas and theresulting reaction mixture was stirred at room temperature for 20 hours.The solids were filtered over a pad of celite and the methanol solutionwas concentrated to give 0.8 g of compound 49 that was redissolved in asolution of 10 mL of trifluoroacetic acid and 30 mL of DCM. Theresulting solution was stirred at room temperature for 1 hour and thevolatiles were removed by using Genevac®. The resulting crude sample waspurified by column chromatography using a gradient of ethylacetate/hexane as eluent to give 0.6 g of compound 50.

d)2-Benzyl-2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isoindole-1,4′-piperidine]-3-one(51): To a DMF (10.0 mL) solution of 0.61 g (2.1 mmol) of the spirocycle50 at room temperature was added 0.6 g (2.1 mmol) of the alkyl chloride9 (Across) and 0.5 mL (2.6 mmol) of diisopropylethyl amine. Theresulting mixture was stirred at 85° C. for 10 hours. The solvent wasremoved by Genevac® and the resulting crude sample was purified bycolumn chromatography using a gradient of ethyl acetate/hexane as eluentto give 126 mg of the title compound 51. MS: m/z 536. ¹H NMR (CDCl₃): δ7.99-7.93 (m, 1H), 7.85-7.80 (m, 1H), 7.55-7.48 (m, 2H), 7.32-7.19 (m,5H), 7.19-7.12 (m, 4H), 7.00-6.92 (m, 4H), 4.80 (s, 2H), 3.92-3.83 (m,1H), 2.89-2.78 (m, 2H), 2.65-2.54 (m, 2H), 2.54-2.45 (m, 2H), 2.28-2.14(m, 2H), 2.08-1.97 (m, 2H), 1.53-1.35 (m, 4H).

1-Benzyl-2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine]-2-onecan be prepared according to the above described procedure using1-benzyl-2,3-dihydro-1′-tert-butoxycarbonyl-spiro[indole-3,4′-piperidine]-2-one(57) prepared in Example 21, step c, as a starting material. LC: 97.4%.MS: m/z=537.3, 538.2 (M+H). ¹H NMR (CDCl₃): δ 7.37-7.33 (m, 1H),7.33-7.22 (m, 5H), 7.21-7.12 (m, 5H), 7.03-6.94 (m, 5H), 6.73-6.69 (m,1H), 4.92-4.85 (s, 1H), 3.94-3.86 (m, 1H), 2.97-2.85 (m, 2H), 2.72-2.61(m, 2H), 2.58-2.49 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1.84 (m, 4H),1.58-1.47 (m, 2H).

Example 212,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine]-2-one(60)

a) To a solution of 10.0 g (58.13 mmol) of 2-bromoaniline 52 in 80 mL of1,2-dichloroethane at room temperature was added 5.8 mL (58.13 mmol) ofbenzaldehyde 53. The resulting mixture was stirred at room temperaturefor 10 hours. After this period, the reaction mixture was diluted with300 mL DCM and washed with saturated aqueous NaHCO₃. The layers wereseparated and the organic layer was dried (Na₂SO₄) and concentrated togive a crude sample that was purified by column chromatography using agradient of ethyl acetate/hexane as eluent to give 6.2 g of compound 54.

b) To a stirred solution of the acid 55 (6.4 g, 27.9 mmol) and pyridine(5.5 mL, 68.06 mmol) in DCM (36 mL) at room temperature was added 2.6 mL(35.1 mmol) of SOCl₂. The resulting mixture was stirred at roomtemperature for 1 hour and a mixture of compound 54 (4.0 g, 15.26 mmol),triethylamine (7.5 mL, 53.87 mmol), and DMAP (187 mg, 1.53 mmol) in DCM(36 mL) were added to it. The reaction mixture was stirred at roomtemperature for 12 hours. After this period, the reaction mixture wasdiluted with 300 mL of DCM and washed with saturated aqueous NaHCO₃. Thelayers were separated and the organic layer was dried (Na₂SO₄) andconcentrated to give a crude sample that was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 3.9 g of compound 56.

c)1-Benzyl-2,3-dihydro-1′-tert-butoxycarbonyl-spiro[indole-3,4′-piperidine]-2-one(57): A 2.5 g (5.28 mmol) portion of compound 56, NaOtBu (761 mg, 7.92mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (Aldrich)(246 mg, 0.395 mmol) was dissolved in 10 mL of dioxane under nitrogen.The reaction mixture was stirred at room temperature for 5 minutes andthen Pd₂ (dba)₃ (242 mg, 0.264 mmol) was added to the mixture. Thereaction mixture stirred at 95° C. for 5 hours and then the volatileswere removed by using Genevac®. The resulting crude sample was purifiedby column chromatography using a gradient of ethyl acetate/hexane aseluent to give 1.1 g of compound 57.

d)2,3-Dihydro-1′-tert-butoxycarbonyl-spiro[indole-3,4′-piperidine]-2-one(58): To a 30 mL of NH₃ that is condensed at −78° C. was added 300 mg ofsodium metal. The mixture was stirred at −78° C. for 5 minutes and asolution of compound 57 (1.1 g, 2.8 mmol) in 6 mL of THF was added tothe mixture. The resulting reaction mixture was stirred for 1 hour andthe reaction was quenched with mL of methanol. The excess NH₃ wasevaporated at room temperature and then the volatiles were removed byusing Genevac®. The resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 0.8 g of compound 58.

e) 2,3-Dihydro-spiro[indole-3,4′-piperidine]-2-one (59): A 1.1 g (2.8mmol) portion of compound 58 was treated with 50 mL of 2 N HCl in ether(Aldrich) at room temperature for 6 hours. After this period, thevolatiles were removed by rotary evaporator to give 0.7 g of compound 59as a white solid.

f)2,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine]-2-one(60): To a DMF (10.0 mL) solution of 0.3 g (1.63 mmol) of the spirocycle59 at room temperature was added 0.5 g (1.63 mmol) of the alkyl chloride9 (Across) and 0.7 mL (4 mmol) of diisopropylethyl amine. The resultingmixture was stirred at 85° C. for 10 hours. The solvent was removed byGenevac® and the resulting crude sample was purified by columnchromatography using a gradient of ethyl acetate/hexane as eluent togive 126 mg of the title compound 60. MS: m/z 447. ¹H NMR (CDCl₃): δ7.37-7.28 (m, 2H), 7.24-7.13 (m, 4H), 7.06-6.87 (m, 4H), 6.87-6.82 (m,2H), 3.92-3.88 (m, 1H), 2.89-2.79 (m, 2H), 2.69-2.59 (m, 2H), 2.56-2.49(m, 2H), 2.10-2.00 (m, 2H), 1.98-1.79 (m, 3H), 1.63-1.44 (m, 2H).

2,3-Dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[isoindole-1,4′-piperidine]-3-onecan be prepared according to the above described procedure using2-benzyl-2,3-dihydro-1′-tert-butoxycarbonyl-spiro[isoindole-1,4′-piperidine]-3-one(48) prepared in Example 20 as a starting material. LC: 100%. MS:m/z=447.3, 448.2 (M+H). ¹H NMR (CDCl₃): δ 7.34-7.79 (m, 1H), 7.61-7.54(m, 1H), 7.50-7.38 (m, 2H), 7.22-7.14 (m, 4H), 7.02-6.94 (m, 4H),6.78-6.72 (s, 1H), 3.93-3.84 (m, 1H), 3.04-2.91 (m, 2H), 2.50-2.39 (m,2H), 2.29-2.15 (m, 2H), 2.15-1.99 (m, 4H), 1.61-1.52 (m, 2H), 1.53-1.45(m, 2H).

Example 221,3-Dihydro-1′-{3-[N,N-bis(4-fluorophenyl)amino]propyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one(68)

a) A 250-mL round bottom flask was charged with Pd₂ (dba)₃ (100 mg), aligand (300 mg; Aldrich), and Cs₂ CO₃ (2.0 g), followed by tert-butanol(25 mL) and 1,4-dioxane (50 mL). After the mixture was stirred for 5minutes, 4-fluoroaniline (61) (1.0 g, 4.5 mmol) and compound 62 (0.6 g,5.4 mmol) were added to the flask. The flask was then flushed withargon, heated, and stirred at 100° C. for hours. When the reaction wascomplete, the flask was removed from the heat and allowed to cool toambient temperature. The residue was concentrated under vacuum andpurified by flash silica column chromatography isocratically (ethylacetate/hexanes, 1:9) to give compound 63 as a yellow oil (0.7 g, yield70%).

b) A 50-mL round bottom flask was charged with compound 63 (0.4 g, 1.95mmol) and compound 64 (0.6 mL, 2.3 mmol; Aldrich) in DMF (6 mL). Themixture was stirred at ambient temperature for 5 minutes, and then NaH(60 mg, 60% in mineral oil) was added. The reaction mixture was heatedto 70° C. for 4 hours. When the reaction was complete, the mixture wasquenched with water (20 mL), transferred to an extraction funnel, andextracted with ethyl acetate (2×20 mL). The organic layers were combinedand dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash silica column chromatography isocratically (ethylacetate/hexanes, 3:100) to give compound 65 as a colorless oil (0.5 g,yield 98%).

c) In a 50 mL vial, compound 65 was re-dissolved in acetonitrile (10 mL)at ambient temperature, and one mL of HF (48% aq.) was added. The vialwas then shaken at ambient temperature for 2 hours. When the reactionwas complete, the reaction mixture was neutralized with 2N aq. NaOH andextracted with ethyl acetate (2×10 mL). The solvents were removed invacuuo to leave the product 66 as a colorless oil. The product was usedin the next step without further purification.

d) In a 50-mL vial, the crude product 66 (0.3 g, 1.1 mmol) was dissolvedin DCM (5 mL) and triethylamine (TEA) (0.2 mL). MeSO₂ Cl (0.12 mL, 1.5mmol) was added to the reaction mixture and the mixture was shaken atambient temperature for 12 hours. When the reaction was complete, theproduct was purified by flash silica column chromatography isocraticallywith ethyl acetate/hexanes (1:4), to afford compound 67 as a colorlessoil (0.35 g, yield 92%).

e) In a 20 mL sealed vial, compound 67 (50 mg, 0.15 mmol) was dissolvedin 2 mL of acetonitrile, followed by addition of compound II (50 mg,0.21 mmol) as its HCl salt, K₂CO₃ (30 mg, 0.21 mmol), and Et₃ N (0.1 mL,0.7 mmol). The mixture was heated to reflux for 6 hours. When thereaction was complete, the residue was concentrated to dryness undervacuum. The desired compound was partitioned with 5 mL of water andethyl acetate (2×10 mL). The organic solution was dried over MgSO₄, andconcentrated under vacuum. The crude residue was purified by flashsilica column chromatography with an isocratic eluent of DCM/MeOH(98:2), to afford the title compound 68 as a white solid (40 mg, yield60%). LC: 100%. MS: m/z=449.2, 450.3 (M+H). ¹H NMR (CDCl₃): δ 7.92-7.85(m, 1H), 7.72-7.64 (m, 1H), 7.57-7.48 (m, 1H), 7.45-7.39 (m, 1H),7.28-6.82 (m, 8H), 3.80-3.63 (m, 2H), 2.95-2.85 (m, 2H), 2.58-2.44 (m,4H), 2.26-2.13 (m, 2H), 1.93-1.79 (m, 2H), 1.78-1.66 (m, 2H).

Example 231,3-Dihydro-1′-[N,N,-bis(4-fluorophenyl)aminocarbonylmethyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one(71)

a) A 50-mL vial was charged with compound 63 (0.2 g, 0.98 mmol) andcompound 69 (110 mg, 0.98 mmol; Aldrich) in 2 mL of toluene and themixture was heated to 80° C. for 3 hours with stirring. When thereaction was complete, the resulting compound was purified on a bed ofsilica gel isocratically with EtOAc/hexanes (2:10) to afford compound 70as a white solid (240 mg, yield 74%).

b) A 50-mL vial was charged with compound 70 (40 mg, 0.14 mmol) andcompound II (34 mg, 0.14 mmol, Arch corporation) in 2 mL of AcN and themixture was heated to 80° C. for 4 hours with stirring. When thereaction was complete, the resulting compound was purified on a bed ofsilica gel isocratically with EtOAc/Hexanes (2:10) to afford the titlecompound 71 as a white solid (20 mg, yield 32%). LC: 100%. MS:m/z=449.2, 450.1 (M+H). ¹H NMR (CDCl₃): δ 7.90-7.84 (m, 1H), 7.71-7.64(m, 1H), 7.56-7.49 (m, 1H), 7.45-7.38 (m, 1H), 7.36-6.97 (m, 8H),3.26-3.18 (m, 2H), 3.11-3.00 (m, 2H), 2.66-2.54 (m, 2H), 2.41-2.27 (m,2H), 1.77-1.63 (m, 2H).

Example 241,3-Dihydro-1′-{2-[N,N,-bis(4-fluorophenyl)aminocarbonyl]ethan-1-oyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one(75)

a) A 50-mL vial was charged with compound 63 (0.3 g, 1.46 mmol) andcompound 72 (0.2 g, 1.46 mmol; Aldrich) in 1 mL of toluene and themixture was heated to 80° C. for 3 hours with stirring. When thereaction was complete, the resulting compound was purified on a bed ofsilica gel isocratically with EtOAc/hexanes (3:7) to afford compound 70as a colorless oil (0.4 g, yield 89%).

b) A 20-mL vial was charged with compound 73 (0.3 g, 0.98 mmol) anddissolved in 4 mL of MeOH. One mL of aq. LiOH (1N aq., 1 mmol) was addedto the mixture and was allowed to react at ambient temperature for 5hours with shaking. When the reaction was complete, the reaction wasquenched with 5 mL of 2N aq. HCl and the compound was extracted with 2×5mL of DCM. The organic layer was dried over Na₂SO₄, concentrated undervacuum, and was purified on a bed of silica gel isocratically withEtOAc/DCM (1:1) to afford compound 74 as a colorless oil (0.25 g, yield87%).

c) A 20-mL vial was charged with compound 74 (0.1 g, 0.34 mmol),compound II (82 mg, 0.34 mmol), DMAP (10 mg), HOBt (20 mg), and TEA (0.2mL), and dissolved in 4 mL of DCM. The mixture was cooled to 0° C. anddiisopropyl azodicarboxylate (DIC) (0.05 mL, 0.34 mmol) was added. Thereaction mixture was shaken for 16 hours while warming to roomtemperature. When the reaction was complete, the residue was purified ona bed of silica gel isocratically with EtOAc/DCM (1:1) to afford thetitle compound 75 as a colorless oil (50 mg, yield 32%). LC: 100%. MS:m/z=477.1, 478.1 (M+H). ¹H NMR (CDCl₃): δ 7.93-7.85 (m, 1H), 7.73-7.64(m, 1H), 7.59-7.51 (m, 1H), 7.50-7.21 (m, 5H), 7.21-6.99 (m, 4H),4.79-4.65 (m, 1H), 3.91-3.75 (m, 1H), 3.66-3.52 (m, 2H), 3.51-3.40 (m,1H), 3.16-3.02 (m, 1H), 2.30-2.14 (m, 1H), 2.15-2.01 (m, 1H), 1.78-1.64(m, 2H).

Example 25

Compounds of the invention have been tested in the calcium mobilizationand/or assay for N-type calcium channel blocking activity, which aredescribed in detail above. Some compounds described have also beentested in the calcium mobilization and/or electrophysiological assaysfor L-type calcium channel blocking activity, which is described indetail above. Representative values are presented in TABLE 2.

TABLE 2 Evaluation of the tested compounds as N-type calcium channel(NTCC) blockers and L-type calcium channel (LTCC) blockers after acalcium mobilization in vitro assay NTCC IC₅₀ LTCC IC₅₀ COMPOUND (μM)(μM) 1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]- 0.46 3.95spiro[isobenzofuran-1,4′-piperidine]-3-one (12)1,3-dihydro-1′-{3-[N,N-bis(4- 0.23 >20fluorophenyl)amino]propyl}-spiro[isobenzofuran- 1,4′-piperidine]-3-one(68) 1,3-dihydro-1′-[6-(2,2,2-trifluoroethoxy)pyridin-3- 6.47 NDylcarbonyl-spiro[isobenzofuran-1,4′-piperidine]-3- one1,3-dihydro-1′-(4-methoxy-3- 6.94 NDtrifluoromethylbenzoyl)-spiro[isobenzofuran-1,4′- piperidine]-3-one1,3-dihydro-1′-{4-methyl-2-[N-methyl-N-(4- 4.13 NDmethoxybenzyl)amino]pentanoyl-spiro[isobenzofuran-1,4′-piperidine]-3-one1-(4,4-bis(4-fluorophenyl)butyl-spiro[piperidine- 0.31 2.724,5′-cyclopenta[b]pyridine] (10)1-(4-isopropylbenzyl)-spiro[piperidine-4,5′- 2.35 10-20cyclopenta[b]pyridine] (21) 1-(N-trifluoromethylcarbonyl-1,2,3,4- 5.61ND tetrahydroisoquinolin-6-yl-sulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine]1,3-dihydro-1′-(3,3-diphenylpropanoyl)- 2.66 NDspiro[isobenzofuran-1,4′-piperidine]-3-one1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butanoyl]- 0.69 0.31spiro[isobenzofuran-1,4′-piperidine]-3-one (14)1,3-dihydro-1′-{2-[N,N-bis(4-fluorophenyl)- 1.64 NDaminocarbonyl]ethyl}-spiro[isobenzofuran-1,4′- piperidine]-3-one1,3-dihydro-1′-{2-[N,N,-bis(4- 5.79 NDfluorophenyl)aminocarbonyl]ethan-1-oyl}-spiro[isobenzofuran-1,4′-piperidine]-3-one (75)1,3-dihydro-1′-[N,N,-bis(4- 4.89 ND fluorophenyl)aminocarbonylmethyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one (71)1,3-dihydro-1′-[4-(4-fluorophenyl)-4-oxo- 10-20 NDbutanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3- one1,3-dihydro-1′-(4-methoxy-3- 10-20 NDtrifluoromethylbenzoyl)-spiro[isobenzofuran-1,4′- piperidine]-3-one1,3-dihydro-1′-(6-methoxypyridin-3-ylcarbonyl)- 10-20 NDspiro[isobenzofuran-1,4′-piperidine]-3-one1,3-dihydro-1′-[4-methyl-2-(N-methyl-N-tert- 10.45 NDbutoxycarbonylamino)pentanoyl]-spiro[isobenzofuran-1,4′-piperidine]-3-one1-(3,3-diphenylpropanoyl)-spiro[piperidine-4,5′- 3.52 NDcyclopenta[b]pyridine 1-(4,4-bis(4-fluorophenyl)-but-3-enoyl)- 0.92 1.61spiro[piperidine-4,5′-cyclopenta[b]pyridine] (17)1-(4,4-bis(4-fluorophenyl)-butanoyl)- 0.85 0.46spiro[piperidine-4,5′-cyclopenta[b]pyridine] (15)1-(4-dimethylaminobenzoyl)-spiro[piperidine-4,5′- 10.05 NDcyclopenta[b]pyridine] (23) 1-(4-methoxy-3-trifluoromethylbenzyl)- 10-20ND spiro[piperidine-4,5′-cyclopenta[b]pyridine]1-(4-isopropylbenzoyl)-spiro[piperidine-4,5′- 10-20 NDcyclopenta[b]pyridine] 1-(4-methoxybenzyl)-spiro[piperidine-4,5′- 2.92ND cyclopenta[b]pyridine] (19)1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 0.55 3.785-ylmethenyl)ethyl]-spiro[piperidine-4,5′- cyclopenta[b]pyridine]1-(benzo[b]thiophen-2-ylcarbonyl)- 10-20 NDspiro[piperidine-4,5′-cyclopenta[b]pyridine]1-(4-trifluoromethylphenylsulfonyl)- 6.12 NDspiro[piperidine-4,5′-cyclopenta[b]pyridine] (25)1-[4,4-bis(4-fluorophenyl)butyl]-6′,7′-dihydro- 0.34 0.71spiro[piperidine-4,5′-cyclopenta[b]pyridine (31)1-[4,4-bis(4-fluorophenyl)butanoyl]-6′,7′-dihydro- 0.67 0.38spiro[piperidine-4,5′-cyclopenta[b]pyridine (36)1-(4-iso-propylbenzyl)-6′,7′-dihydro- 4.30 NDspiro[piperidine-4,5′-cyclopenta[b]pyridine (38)1-(3-trifluoromethyl-4-methoxyphenyl)-6′,7′- 4.34 NDdihydro-spiro[piperidine-4,5′- cyclopenta[b]pyridine (40)1-[4,4-bis(4-fluorophenyl)but-3-enoyl]- 5.59 NDspiro[piperidine-4,1′-indene] (33) 1-[4,4-bis(4-fluorophenyl)butanoyl]-10-20 ND spiro[piperidine-4,1′-indene] (34)1-(methoxybenzyl)-spiro[piperidine-4,1′-indene] 0.82 5.44 (37)1-(3-trifluoromethyl-4-methoxybenzoyl)- 2.29 5.74spiro[piperidine-4,1′-indene] 1-[4,4-bis(4-fluorophenyl)butanoyl]-4.92 >20 spiro[piperidine-4,1′-indane] (35)1,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]- 1.20 2.56spiro[isobenzofuran-1,4′-piperidine] (42)2-benzyl-2,3-dihydro-1′-[4,4-bis(4- 0.55 6.39fluorophenyl)butyl]-spiro[isoindole-1,4′- piperidine]-3-one (51)2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]- 0.34 >20spiro[isoindole-1,4′-piperidine]-3-one2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]- 1.05 3.80spiro[indole-3,4′-piperidine] (60) 1-benzyl-2,3-dihydro-1′-[4,4-bis(4-3.14 >20 fluorophenyl)butyl]-spiro[indole-3,4′-piperidine] ND = notdetermined

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, and —C(O)Y, wherein Y ishydroxy, alkoxy, amino, alkylamino, or dialkylamino; Q¹ is —C(O)— orCR²⁰R²⁴; Q² is —C(O)—, CR²¹R²², or N—R²⁶; and Q³ is CR²³ or N; providedthat when Q³ is N, then Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²²; when Q¹ isCR²⁰R²⁴, then Q² is —C(O)— or CR²¹R²², and Q³ is CR²³; and when Q² isN—R²⁶, then Q¹ is —C(O)— and Q³ is CR²³; R²⁰, R²¹, R²², and R²⁴ are eachindependently selected from the group consisting of hydrogen and alkyl;or R²⁰ and R²¹ together form a bond and R²² and R²⁴ are independentlyhydrogen or alkyl; R²³ is hydrogen or alkyl; R²⁶ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, phenyl, benzyl, and phenethyl, wherein the phenylring of any of the phenyl, benzyl and phenethyl groups is optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, and haloalkyl; Z is selectedfrom the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵, wherein: Z¹ is

Z² is—CR³R⁴—(CH₂)_(n)-D—R⁹; Z³ is—SO₂—R¹⁰; Z⁴ is

and Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O; R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁹ is selectedfrom the group consisting of phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or twosubstituents in adjacent carbon atoms in the phenyl ring optionally forma bridge —O—CH₂—O—; and pyridyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,haloalkyl, halogen, haloalkoxy, and alkoxy; or -D—R⁹ together forms

R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl, mercaptoalkyl,aminoalkyl; phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, and haloalkyl; and benzyl, wherein the phenyl ring isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; R¹³ is hydrogen and R¹⁴ is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, andaminoalkyl; R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl; A is —C(O)—, CH₂, or is absent, and Bis CH or N; or A-B is CH═C (where CH is attached to —(CH₂)_(m)—); D is—C(O)— or is absent; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and pis 0 or 1; with the following provisos when Q³ is CR²³: 1) when Q¹ isCR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, or Q¹ is CR²⁰R²⁴ or —C(O)— and Q²is CR²¹R²², Z is Z¹, A is CH₂ or absent, and B is CH, then R³ and R⁴together form ═O; 2) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, orQ¹ is CR²⁰R²⁴ or —C(O)— and Q² is CR²¹R²², Z is Z², n is 0 or 1, and Dis absent, then R⁹ is not an optionally substituted phenyl; 3) when Q¹is CR²⁰R²⁴, Q² is CR²¹R²², and Z is Z³, then R¹⁰ is not an optionallysubstituted phenyl; 4) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²², where R²⁰and R²¹ together form a bond, and Z is Z², then -D-R⁸ does not togetherform

or 5) when Q¹ is —C(O)—, Q² is N—R²⁶, and Z is Z², then R³ and R⁴together form ═O.
 2. The compound of claim 1 having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, halogen, and —C(O)Y, wherein Y ishydroxy, alkoxy, amino, alkylamino, or dialkylamino; Q¹ is CHR²⁰; Q² isCR²¹R²²; and Q³ is N; wherein R²⁰ and R²¹ together form a bond, and R²²is hydrogen or alkyl; Z is selected from the group consisting of Z¹, Z²,Z³, Z⁴, and Z⁵, wherein Z¹ is

Z² is—CR³R⁴—(CH₂)_(n)-D—R⁹; Z³ is—SO₂—R¹⁰; Z⁴ is

and Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O; R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁹ is selectedfrom the group consisting of phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or twosubstituents in adjacent carbon atoms of the phenyl ring optionally forma bridge —O—CH₂—O—; and pyridyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,haloalkyl, halogen, haloalkoxy, and alkoxy; or -D-R⁹ together forms

R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl, alkylthiol,aminoalkyl; phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, and haloalkyl; and benzyl, wherein the phenyl ring isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; R¹³ is hydrogen and R¹⁴ is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, andaminoalkyl; R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl; A is —C(O)—, CH₂, or is absent, and Bis CH or N; or A-B is CH═C (where CH is attached to —(CH₂)_(m)—); D is—C(O)— or is absent; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and pis 0 or
 1. 3. The compound of claim 1, having a) the Formula III:

wherein R¹, R², R²², R²⁴ and Z are as defined in claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof; or b) theFormula IV:

wherein R¹, R², R²⁰, R²¹, R²², R²⁴ and Z are as defined in claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof; or c) theFormula V:

wherein R¹, R², R²⁰, R²¹, R²², R²³, R²⁴ and Z are as defined in claim 1,or a pharmaceutically acceptable salt, prodrug or solvate thereof; or d)the Formula VI:

wherein R¹, R², R²², R²³, R²⁴ and Z are as defined in claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof; or e) theFormula IX:

wherein R¹, R², R²³, R²⁶, and Z are as defined in claim 1, or apharmaceutically acceptable salt, prodrug or solvate thereof; or f) theFormula XIV:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined in claim 1; or g) the FormulaXVI:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined in claim 1; or h) the FormulaXVIII:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined in claim 1, with the provisothat when A is CH₂ or absent and B is CH, then R³ and R⁴ together form═O; or i) the Formula XX:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, A, B, and m are as defined in claim 1, with the provisothat when A is CH₂ or absent and B is CH, then R³ and R⁴ together form═O; or j) the Formula XXVI:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein R³-R⁸, R²⁶, A, B, and m are as defined in claim
 1. 4. Thecompound of claim 3, wherein Z is Z¹, Z², Z³, Z⁴ or Z⁵.
 5. The compoundof claim 3, wherein R¹ and R² are both hydrogen.
 6. The compound ofclaim 3, wherein R²⁶ is hydrogen or unsubstituted benzyl.
 7. Thecompound of claim 1, wherein a) R³ and R⁴ together form ═O and Z is Z¹;or b) R³ and R⁴ are both hydrogen and Z is Z² and n is
 0. 8. Thecompound of claim 1, wherein Z is Z² and -D-R⁹ together forms


9. The compound of claim 4, wherein a) Z is Z¹ and R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, hydroxy, cyano, amino, alkylamino,and dialkylamino; or b) Z is Z² and i. R⁹ is phenyl optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, alkylamino, anddialkylamino; or ii. R⁹ is pyridyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, haloalkyl, halogen, haloalkoxy, and alkoxy; or c) Z is Z³ and i.R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or ii. R¹⁰ is 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; d) Z is Z⁴ and i. R¹¹ andR¹² are each independently selected from the group consisting ofhydrogen; alkyl; alkoxycarbonyl; phenyl optionally substituted with oneor two substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, and haloalkyl; and benzyl optionally substitutedat the phenyl ring with one or two substituents independently selectedfrom the group consisting of alkyl, alkoxy, halogen, and haloalkyl; orii. R¹⁴ is selected from the group consisting of alkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, and aminoalkyl; or e) Z is Z⁵ and R¹⁵ isselected from the group consisting of 2-benzo[b]thienyl,3-benzo[b]thienyl, 1-benzo[c]thienyl, 3-benzo[c]thienyl, 2-benzofuryl,3-benzofuryl, 1-isobenzofuryl, and 3-isobenzofuryl.
 10. The compound ofclaim 1, which is:1-(4,4-bis(4-fluorophenyl)butyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(3,3-diphenylpropanoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4,4-bis(4-fluorophenyl)-but-3-enoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4,4-bis(4-fluorophenyl)butanoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-dimethylaminobenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-isopropylbenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-methoxy-3-trifluoromethylbenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-isopropylbenzoyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-methoxybenzyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylmethenyl)ethyl]-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(benzo[b]thiophen-2-ylcarbonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(N-trifluoromethylcarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl-sulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-trifluoromethylphenylsulfonyl)-spiro[piperidine-4,5′-cyclopenta[b]pyridine];or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 11. Acompound wherein said compound is:1-[4,4-bis(4-fluorophenyl)butyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-[4,4-bis(4-fluorophenyl)butanoyl]-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(4-iso-propylbenzyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-(3-trifluoromethyl-4-methoxyphenyl)-6′,7′-dihydro-spiro[piperidine-4,5′-cyclopenta[b]pyridine];1-[4,4-bis(4-fluorophenyl)but-3-enoyl]-spiro[piperidine-4,1′-indene];1-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indene];1-(methoxybenzyl)-spiro[piperidine-4,1′-indene];1-(3-trifluoromethyl-4-methoxybenzoyl)-spiro[piperidine-4,1′-indene];1-[4,4-bis(4-fluorophenyl)butanoyl]-spiro[piperidine-4,1′-indane];2,3-dihydro-1′-[4,4-bis(4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine];1-benzyl-2,3-dihydro-1′-[4,4-bis[4-fluorophenyl)butyl]-spiro[indole-3,4′-piperidine];or a pharmaceutically acceptable salt, prodrug or solvate thereof. 12.The compound of claim 1, wherein said compound has an IC₅₀ of about 100μM or less for N-type calcium channel blocking activity in a calciummobilization and/or electrophysiological assay.
 13. A pharmaceuticalcomposition, comprising a compound of claim 1, or a pharmaceuticallyacceptable, salt, prodrug or solvate thereof, and a pharmaceuticallyacceptable carrier.
 14. A method of treating, preventing or amelioratinga disorder responsive to the blockade of calcium channels in a mammalsuffering from said disorder, comprising administering to a mammal inneed of such treatment, prevention or amelioration an effective amountof a compound of Formula I set forth in claim 1, or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof.
 15. The method of claim14, wherein said disorder is pain.
 16. A method of treating, preventingor ameliorating stroke, neuronal damage resulting from head trauma,epilepsy, chronic pain, neuropathic pain, migraine, a mood disorder,schizophrenia, a neurodegenerative disorder, depression, anxiety, apsychosis, hypertension or cardiac arrhythmia in a mammal, comprisingadministering an effective amount of a compound of Formula I to a mammalin need of such treatment, prevention or amelioration, said compound ofFormula I having the structure:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, and —C(O)Y, wherein Y ishydroxy, alkoxy, amino, alkylamino, or dialkylamino; Q¹ is —C(O)— orCR²⁰R²⁴; Q² is —C(O)—, CR²¹R²², or N—R²⁶; and Q³ is CR²³ or N; providedthat when Q³ is N, then Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²²; when Q¹ isCR²⁰R²⁴, then Q² is —C(O)— or CR²¹R²², and Q³ is CR²³; and when Q² isN—R²⁶, then Q¹ is —C(O)— and Q³ is CR²³; R²⁰, R²¹, R²², and R²⁴ are eachindependently selected from the group consisting of hydrogen and alkyl;or R²⁰ and R²¹ together form a bond and R²² and R²⁴ are independentlyhydrogen or alkyl; R²³ is hydrogen or alkyl; R²⁶ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, phenyl, benzyl, and phenethyl, wherein the phenylring of any of the phenyl, benzyl and phenethyl groups is optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, and haloalkyl; Z is selectedfrom the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵, wherein: Z¹ is

Z² is—CR³R⁴—(CH₂)_(n)-D-R⁹; Z³ is—SO₂—R¹⁰; Z⁴ is

and Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O; R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁹ is selectedfrom the group consisting of phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or twosubstituents in adjacent carbon atoms in the phenyl ring optionally forma bridge —O—CH₂—O—; and pyridyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,haloalkyl, halogen, haloalkoxy, and alkoxy; or -D-R⁹ together forms

R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl, mercaptoalkyl,aminoalkyl; phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, and haloalkyl; and benzyl, wherein the phenyl ring isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; R¹³ is hydrogen and R¹⁴ is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, andaminoalkyl; R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl; A is —C(O)—, CH₂, or is absent, and Bis CH or N; or A-B is CH═C (where CH is attached to —(CH₂)_(m)—); D is—C(O)— or is absent; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and pis 0 or 1; with the following provisos when Q³ is CR²³: 1) when Q¹ isCR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, or Q¹ is CR²⁰R²⁴ or —C(O)— and Q²is CR²¹R²², Z is Z¹, A is CH₂ or absent, and B is CH, then R³ and R⁴together form ═O; 2) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²² or —C(O)—, orQ¹ is CR²⁰R²⁴ or —C(O)— and Q² is CR²¹R²², Z is Z², n is 0 or 1, and Dis absent, then R⁹ is not an optionally substituted phenyl; 3) when Q¹is CR²⁰R²⁴, Q² is CR²¹R²², and Z is Z³, then R¹⁰ is not an optionallysubstituted phenyl; 4) when Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²², where R²⁰and R²¹ together form a bond, and Z is Z², then -D-R⁹ does not togetherform

or 5) when Q¹ is —C(O)—, Q² is N—R²⁶, and Z is Z², then R³ and R⁴together form ═O.
 17. A method of modulating calcium channels in amammal, comprising administering to the mammal at least one compound ofFormula I having the structure:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, and —C(O)Y, wherein Y ishydroxy, alkoxy, amino, alkylamino, or dialkylamino; Q¹ is —C(O)— orCR²⁰R²⁴; Q² is —C(O)—, CR²¹R²², or N—R²⁶; and Q³ is CR²³ or N; providedthat when Q³ is N, then Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²²; when Q¹ isCR²⁰R²⁴, then Q² is —C(O)— or CR²¹R²², and Q³ is CR²³; and when Q² isN—R²⁶, then Q¹ is —C(O)— and Q³ is CR²³; R²⁰, R²¹, R²², and R²⁴ are eachindependently selected from the group consisting of hydrogen and alkyl;or R²⁰ and R²¹ together form a bond and R²² and R²⁴ are independentlyhydrogen or alkyl; R²³ is hydrogen or alkyl; R²⁶ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, phenyl, cycloalkyl, benzyl, and phenethyl, wherein the phenylring of any of the phenyl, benzyl and phenethyl groups is optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, and haloalkyl; Z is selectedfrom the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵, wherein: Z¹ is

Z² is—CR³R⁴—(CH₂)_(n)-D-R⁹; Z³ is—SO₂—R¹⁰; Z⁴ is

and Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O; R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁹ is selectedfrom the group consisting of phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or twosubstituents in adjacent carbon atoms in the phenyl ring optionally forma bridge —O—CH₂—O—; and pyridyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,haloalkyl, halogen, haloalkoxy, and alkoxy; or -D-R⁹ together forms

R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl, mercaptoalkyl,aminoalkyl; phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, and haloalkyl; and benzyl, wherein the phenyl ring isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; R¹³ is hydrogen and R¹⁴ is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, andaminoalkyl; R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl; A is —C(O)—, CH₂, or is absent, and Bis CH or N; or A-B is CH═C (where CH is attached to —(CH₂)_(m)—); D is—C(O)— or is absent; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and pis 0 or
 1. 18. A compound of Formula I having the structure:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, and —C(O)Y, wherein Y ishydroxy, alkoxy, amino, alkylamino, or dialkylamino; Q¹ is —C(O)— orCR²⁰R²⁴; Q² is —C(O)—, CR²¹R²², or N—R²⁶; and Q³ is CR²³ or N; providedthat when Q³ is N, then Q¹ is CR²⁰R²⁴ and Q² is CR²¹R²²; when Q¹ isCR²⁰R²⁴, then Q² is —C(O)— or CR²¹R²², and Q³ is CR²³; and when Q² isN—R²⁶, then Q¹ is —C(O)— and Q³ is CR²³; R²⁰, R²¹, R²², and R²⁴ are eachindependently selected from the group consisting of hydrogen and alkyl;or R²⁰ and R²¹ together form a bond and R²² and R²⁴ are independentlyhydrogen or alkyl; R²³ is hydrogen or alkyl; R²⁶ is selected from thegroup consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, phenyl, benzyl, and phenethyl, wherein the phenylring of any of the phenyl, benzyl and phenethyl groups is optionallysubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkoxy, halogen, and haloalkyl; Z is selectedfrom the group consisting of Z¹, Z², Z³, Z⁴, and Z⁵, wherein: Z¹ is

Z² isCR³R⁴—(CH₂)_(n)-D-R⁹; Z³ is—SO₂—R¹⁰; Z⁴ is

and Z⁵ is

R³ and R⁴ are both hydrogen or together form ═O; R⁵, R⁶, R⁷ and R⁸ areeach independently selected from the group consisting of hydrogen,alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino; R⁹ is selectedfrom the group consisting of phenyl optionally substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl,cyano, amino, aminoalkyl, alkylamino, and dialkylamino, or twosubstituents in adjacent carbon atoms in the phenyl ring optionally forma bridge —O—CH₂—O—; and pyridyl optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,haloalkyl, halogen, haloalkoxy, and alkoxy; or -D-R⁹ together forms

R¹⁰ is phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, andalkylcarbonylamino; or 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl optionally substituted at the nitrogenatom with alkylcarbonyl or haloalkylcarbonyl; R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkoxycarbonyl, hydroxyalkyl, haloalkyl, mercaptoalkyl,aminoalkyl; phenyl optionally substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, and haloalkyl; and benzyl, wherein the phenyl ring isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen, andhaloalkyl; R¹³ is hydrogen and R¹⁴ is selected from the group consistingof hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, andaminoalkyl; R¹⁵ is selected from the group consisting of alkylthioalkyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 1-benzo[c]thienyl,3-benzo[c]thienyl, 2-benzofuryl, 3-benzofuryl, 1-isobenzofuryl,3-isobenzofuryl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl,1-piperidinyl, and 1-pyrrolidinyl; A is —C(O)—, CH₂, or is absent, and Bis CH or N; or A-B is CH═C (where CH is attached to —(CH₂)_(m)—); D is—C(O)— or is absent; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; and pis 0 or 1; wherein said compound is radiolabeled.
 19. A method forscreening a candidate compound for the ability to bind to a receptorusing the radiolabeled compound of claim 18, comprising: a) introducinga fixed concentration of the radiolabeled compound to the receptor toform a mixture; b) titrating the mixture with the candidate compound;and c) determining the binding of the candidate compound to saidreceptor. 20-21. (canceled)
 22. The method of claim 15, wherein saiddisorder is chronic pain, acute pain, or surgical pain.